New derivatives of 2-(iminomethyl)amino-phenyl, their preparation, their use as medicaments and the pharmaceutical compositions containing them

ABSTRACT

The invention relates to new derivatives of 2-(iminomethyl)amino-phenyl which are NO synthase inhibitors and can trap reactive oxygen species. These compounds can notably be used for the treatment of stroke, of neurodegenerative diseases and of ischemic or hemorragic cardiac or cerebral infarctions.  
     These compounds include:  
     N-{4-[({[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}amino)methyl]phenyl}thiophene-2-carboximidamide;  
     N-{3-[({[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}amino)methyl]phenyl}thiophene-2-carboximidamide;  
     N-(4-{[{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}(methyl)amino]methyl}phenyl)thiophene-2-carboximidamide;  
     N-[3-({[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propyl]amino}methyl) phenyl]thiophene-2-carboximidamide;  
     N-(3-{[(3,5-di-tert-butyl-4-hydroxybenzyl)amino]methyl}phenyl) thiophene-2-carboximidamide;  
     N-[3-({[2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethyl]amino}methyl) phenyl]thiophene-2-carboximidamide;  
     N-[3-({[3-(4-hydroxy-3,5-diisopropylphenyl)propyl]amino}methyl) phenyl]thiophene-2-carboximidamide;  
     N-(3-{[(4-hydroxy-3,5-diisopropylbenzyl)amino]methyl}phenyl) thiophene-2-carboximidamide;  
     N-[3-({[2-(4-hydroxy-3,5-diisopropylphenyl)ethyl]amino}methyl) phenyl]thiophene-2-carboximidamide;  
     N-2-(3,5-di-tert-butyl-4-hydroxybenzoyl)-N-1-(4-{[imino(thien-2-yl)methyl]amino}phenyl)-L-leucinamide;  
     and pharmaceutically acceptable salts thereof.

[0001] A subject of the present invention is new derivatives of2-(iminomethyl)amino-phenyl which have an inhibitory activity onNO-synthase enzymes producing nitrogen monoxide NO and/or an activitywhich traps the reactive oxygen species (ROS). The invention relates tothe derivatives corresponding to general formula (I) defined below,their preparation methods, the pharmaceutical preparations containingthem and their use for therapeutic purposes, in particular their use asNO-synthase inhibitors and selective or non selective traps for reactiveoxygen species.

[0002] Given the potential role of NO and the ROS's in physiopathology,the new derivatives described corresponding to general formula (I) mayproduce beneficial or favourable effects in the treatment of pathologieswhere these chemical species are involved. In particular:

[0003] cardio-vascular and cerebro-vascular disorders including forexample artherosclerosis, migraine, arterial hypertension, septic shock,ischemic or hemorragic cardiac or cerebral infarctions, notably thoserelated with complications of coronary artery bypass grafting, ischemiasand thromboses.

[0004] disorders of the central or peripheral nervous system such as forexample neurodegenerative diseases where there can in particular bementioned cerebral infarctions, sub-arachnoid haemorrhaging, ageing,senile dementias including Alzheimer's disease, Huntington's chorea,Parkinson's disease, Creutzfeld Jacob disease and prion diseases,amyotrophic lateral sclerosis but also pain, cerebral and bone marrowtraumas, addiction to opiates, alcohol and addictive substances,erective and reproductive disorders, cognitive disorders,encephalopathies, encephalopathies of viral or toxic origin.

[0005] disorders of the skeletal muscle and neuromuscular joints(myopathy, myosis) as well as cutaneous diseases.

[0006] proliferative and inflammatory diseases such as for exampleartherosclerosis, pulmonary hypertension, respiratory distress,glomerulonephritis, portal hypertension, psoriasis, arthrosis andrheumatoid arthritis, fibroses, amyloidoses, inflammations of thegastro-intestinal system (colitis, Crohn's disease) or of the pulmonarysystem and airways (asthma, sinusitis, rhinitis).

[0007] organ transplants.

[0008] auto-immune and viral diseases such as for example lupus, AIDS,parasitic and viral infections, diabetes, multiple sclerosis.

[0009] cancer.

[0010] neurological diseases associated with intoxications (Cadmiumpoisoning, inhalation of n-hexane, pesticides, herbicides), associatedwith treatments (radiotherapy) or disorders of genetic origin (Wilson'sdisease).

[0011] all the pathologies characterized by an excessive production ordysfunction of NO and/or ROS's.

[0012] In all these pathologies, there is experimental evidencedemonstrating the involvement of NO or ROS's (J. Med. Chem. (1995) 38,4343-4362; Free Radic. Biol. Med. (1996) 20, 675-705; The Neuroscientist(1997) 3, 327-333).

[0013] Furthermore, NO Synthase inhibitors, their use and more recentlythe combination of these inhibitors with products having antioxidant orantiradicular properties have already been described in previous Patents(respectively U.S. Pat. No. 5,081,148; U.S. Pat. No. 5,360,925 and anunpublished Patent Application).

[0014] A subject of the present invention is the derivatives of2-(iminomethyl)amino-phenyl, their preparation and their therapeuticuse.

[0015] The compounds of the invention correspond to general formula (I):

[0016] in which:

[0017] A represents a hydrogen atom or:

[0018] either a

[0019] radical in which R₁ and R₂ represent, independently, a hydrogenatom, a halogen, the OH group, a linear or branched alkyl or alkoxyradical having from 1 to 6 carbon atoms,

[0020] R₃ represents a hydrogen atom, a linear or branched alkyl radicalhaving from 1 to 6 carbon atoms or a —COR₄ radical,

[0021] R₄ represents a linear or branched alkyl radical having from 1 to6 carbon atoms,

[0022] or a

[0023] radical in which R₃ represents a hydrogen atom, a linear orbranched alkyl radical having from 1 to 6 carbon atoms or a —COR₄radical,

[0024] R₄ represents a linear or branched alkyl radical having from 1 to6 carbon atoms,

[0025] or a

[0026] radical in which R₅ represents a hydrogen atom, the OH group or alinear or branched alkyl or alkoxy radical having from 1 to 6 carbonatoms;

[0027] B represents a linear or branched alkyl radical having from 1 to6 carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 memberscontaining from 1 to 4 heteroatoms chosen from O, S, N and in particularthe thiophene, furan, pyrrole or thiazole radicals, the aryl radicalbeing optionally substituted by one or more groups chosen from thelinear or branched alkyl, alkenyl or alkoxy radicals having from 1 to 6carbon atoms;

[0028] X represents -Z₁-, -Z₁-CO—, —CH═, —CH═CH—CO—, -Z₁-NR₃—CO-Z′₁-,—CO—NR₃-Z′₁-, -Z₁-NR₃—CS—, -Z₁-NR₃—SO₂— or a single bond;

[0029] Het does not exist or represents a heterocycle containing from 1to 5 heteroatoms chosen from O, N, S which can be substitued by one ormore substituents X′—OR₃, X′—NR₃, X′—S—R₃ and such as for example:

[0030] oxetane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene,tetrahydrothiophene, sulpholane, imidazole, imidazoline,dihydroimidazole-2-one, dihydroimidazole-2-thione, oxazole, isoxazole,oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole,thiazoline, thiazolidine, thiazolidinone, hydantoine, 1,2,4-triazole,1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxyde-1,2,5-thiadiazolidine,1,2,4-triazole-3-one, tetrazole, tetrahydropyridine, piperazine,homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine or4-aminopiperidine;

[0031] Y represents a radical chosen from the -Z₂-Q-, -Z₂-CO—,-Z₂-NH—CO—, -Z₂-CH₂—NR₃—CO—, —NR₃-Z₂-Q-, —NR₃—CO-Z₂-Q-, —NR₃—NH—CO-Z₂-,—NH—NH-Z₂-, —NR₃—O-Z₂-, —NR₃—SO₂—NR₃-Z₂-, —O-Z₂-Q-, —O—CO-Z₂-Q- or—S-Z₂-Q-radicals,

[0032] in which Q represents a single bond, O-Z₃, R₃—N-Z₃ or S-Z₃;

[0033] Z₁, Z′₁, Z₂ and Z₃ represent independently a single bond or alinear or branched alkylene radical having from 1 to 6 carbon atoms;preferably, Z₁, Z′₁, Z₂ and Z₃ represent —(CH₂)_(m)—, m being an integercomprised between 0 and 6;

[0034] R₆ represents a hydrogen atom or an OH group;

[0035] it being understood that when Het is absent, then A is not ahydrogen atom and that when A is hydrogen then Het does not represent apiperidine, pyrrolidine or morpholine radical;

[0036] or are salts of the latter.

[0037] The compounds of general formula (I) containing an asymmetricalcentre are of isomeric form. The racemic and enantiomeric forms of thesecompounds also form part of this invention.

[0038] The compounds of the invention can exist in the state of bases orof addition salts in particular with organic or inorganic acids or withbases, and in particular in the state of hydrates, hydrochlorides,dihydrochlorides, fumarates or hemifumarates.

[0039] By linear or branched alkyl having from 1 to 6 carbon atoms ismeant in particular the methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl,isohexyl radicals. By linear or branched alkoxy having from 1 to 6carbon atoms is meant radicals the alkyl radical of which has themeaning indicated previously. By halogen is meant fluorine, chlorine,bromine or iodine atoms.

[0040] Preferably, the compounds of general formula (I) are such thatthey include at least one of the following features:

[0041] A represents a

[0042] radical in which R₁ and R₂ represent, independently, a branchedalkyl radical having from 3 to 6 carbon atoms,

[0043] R₃ represents a hydrogen atom, a linear or branched alkyl radicalhaving from 1 to 6 carbon atoms or a —COR₄ radical,

[0044] R₄ represents a linear or branched alkyl radical having from 1 to6 carbon atoms,

[0045] or A represents a

[0046] radical in which R₃ represents a hydrogen atom or a linear orbranched alkyl radical having from 1 to 6 carbon atoms;

[0047] B represents a thiophene or phenyl radical;

[0048] X represents -Z₁-CO— or —CO—NR₃-Z′₁-;

[0049] Het is absent or represents a piperazine or tetrahydropyridinylradical;

[0050] Y represents -Z₂-Q- or —NR₃-Z₂-Q-;

[0051] R₆ represents a hydrogen atom.

[0052] A particular subject of the invention is the following compoundsof general formula (I), described in the examples (in the form of saltsin certain cases):

[0053] 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-benzamide;

[0054] 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;

[0055]4-acetoxy-3,5-dimethoxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;

[0056]3,5-dimethoxy-4-hydroxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;

[0057]3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;

[0058]4-acetoxy-3,5-dimethoxy-N-{4-[2-[(2-thienyl-(imino)methyl)-amino]phenyl]ethyl}-benzamide;

[0059]3,5-dimethoxy-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)-amino]phenyl]ethyl}-benzamide;

[0060]3,4,5-trihydroxy-N-{4-[2-[(2-thienyl(imino)methyl)-amino]phenyl]ethyl}-benzamide;

[0061]N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamide;

[0062]N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

[0063]N-{4-[4-[3,5-dimethoxy-4-hydroxybenzoyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamide;

[0064] 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-2H-1-benzopyran-2-carboxamide;

[0065]N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

[0066]N-{4-[4-[(5-methoxy-1H-indol-3-yl)methylcarbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

[0067]N-[4-[4-[{3-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-oxo-2-propenyl}-1-piperazinyl]-phenyl]]-2-thiophenecarboximidamide;

[0068]3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{3-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;

[0069]N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-urea;

[0070]N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}amino]-2-hydroxyphenyl]-2-thiophenecarboximidamide;

[0071]N-[3-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}-amino]-4-hydroxyphenyl]-2-thiophenecarboximidamide;

[0072]N-{4-[4-[3,4,5-trihydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

[0073]N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}carbonylamino}-urea;

[0074]N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-thiourea;

[0075]N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{2-{4-[(2-thienyl(imino)methyl)amino]phenyl)ethyl}-urea;

[0076]N-(4-{4-[(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamide;

[0077]N-[4-{4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1H-1,4-diazepin-1-yl}phenyl]-2-thiophenecarboximidamide;

[0078](R)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

[0079](S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

[0080]3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{2-[3-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;

[0081]N-{4-(4-[2-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-ethyl]-1-piperazinyl)phenyl}-2-thiophene-carboximidamide;

[0082] 2-{4-[(2-thienyl(imino)methyl)amino]phenyl ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate;

[0083] 2-{3-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate;

[0084] 2-{2-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate;

[0085] N-[4-(1H-imidazol-1-yl)phenyl]-2-thiophenecarboximidamide;

[0086] N-[4-(3-thiazolidinylmethyl)phenyl]-2-thiophenecarboximidamide;

[0087]N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamide;

[0088] N-[4-(1H-imidazol-1-yl methyl)phenyl]-2-thiophenecarboximidamide;

[0089]N-[4-{2-(3-thiazolidinyl)ethyl}phenyl]-2-thiophenecarboximidamide;

[0090]N-{4-[2-(1H-imidazol-1-yl)ethyl]phenyl}-2-thiophenecarboximidamide;

[0091]N-{4-[2-(1,2,3,6-tetrahydropyridin-1-yl)ethyl]phenyl}-2-thiophenecarboximidamide;

[0092]N-[4-(3-thiazolidinylcarbonylmethyl)phenyl]-2-thiophenecarboximidamide;

[0093]N-(4-{[2-thiazolidinyl]carbonylaminomethyl}phenyl)-2-thiophenecarboximidamide;

[0094]N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-[4-{imino(2-thienyl)-methylamino)phenyl]-2-furancarboxamide;

[0095]3-(3,5-di-t-butyl-4-hydroxyphenyl)-1-[4-{imino(2-thienyl)-methylamino}phenyl]-2,5-imidazolidinedione;

[0096]2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-[4-{imino(2-thienyl)-methylamino}phenyl]-4-thiazolidinone;

[0097]5-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-[4-{imino(2-thienyl)methylamino}phenyl]-2,4-imidazolidinedione;

[0098]2-(S)-4-(S)-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)-phenyl]-4-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-prolinamide;

[0099]5,6-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1-(2H)-pyridinecarboxamide;

[0100]N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(R.S)-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-(R)-thiazolidinecarboxamide;

[0101]N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-thiazolecarboxamide;

[0102]N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine-2-(R)-carboxamide;

[0103] methyl1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)carbonyl]-4-(S)-{4-[(imino(2-thienyl)methyl)amino]-phenoxy}-pyrrolidine-2-(S)-carboxylate;

[0104]1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1I]-benzopyran-2-yl)carbonyl]-3-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine;

[0105]3-{[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]amino}-1-{4-[(imino(2-thienyl)methyl)amino]phenyl}pyrrolidine;

[0106]4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]benzoyl}-N-methyl-1H-imidazole-2-methanamine;

[0107]N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1H-pyrrole-2-carboxamide;

[0108]1-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-{[4-[[imino(2-thienyl)methyl]amino]phenyl]carbonyl}-2-imidazolidinone;

[0109]3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-5-isoxazoleacetamide;

[0110]4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2-thiazolemethanamine;

[0111]4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-1H-imidazole-2-methanamine;

[0112]3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-{2-{4-[(imino(2-thienyl)methyl)amino]phenoxy}ethyl}isoxazole;

[0113]1-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]amino}-carbonyl}-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidine;

[0114]1-(2-hydroxy-5-methoxybenzoyl)-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidine;

[0115]1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-4-[4-[(imino(2-thienyl)methyl)amino]phenoxy}-piperidine;

[0116]1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-{4-[(imino(2-thienyl)methyl)amino]-phenoxy}azetidine;

[0117] as well as their salts, in particular their hydrochlorides,dihydrochlorides, fumarates or hemi-fumarates.

[0118] In a preferential manner, the compounds according to theinvention will be one of the following compounds:

[0119]3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamide;

[0120]3,4,5-trihydroxy-N-{4-[2-[(2-thienyl(imino)methyl)-amino]phenyl]ethyl}-benzamide;

[0121]N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

[0122]N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

[0123] 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[(2-thienyl(imino)methyl)amino]phenyl 1-2H-1-benzopyran-2-carboxamide;

[0124]N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl1-2-thiophenecarboximidamide;

[0125] N-{4-[4-[(5methoxy-1H-indol-3-yl)methylcarbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

[0126]3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{3-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide;

[0127]N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-urea;

[0128]N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}-amino]-2-hydroxyphenyl]-2-thiophenecarboximidamide;

[0129]N-[3-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}-amino]-4-hydroxyphenyl]-2-thiophenecarboximidamide;

[0130]N-{4-[4-[3,4,5-trihydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

[0131]N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl]carbonylamino}-urea;

[0132] or a salt of one of the latter, in particular a hydrochloride,dihydrochloride, fumarate or hemi-fumarate of one of the latter.

[0133] Other preferred compounds for the invention will be the followingcompounds:

[0134]4-acetoxy-3,5-dimethoxy-N-{4-[2-[(2-thienyl-(imino)methyl)-amino]phenyl]ethyl}-benzamide;

[0135]3,5-dimethoxy-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)amino]phenyl]ethyl}-benzamide;

[0136] or a salt of one of the latter, in particular a hydrochloride,dihydrochloride, fumarate or hemi-fumarate of one of the latter.

[0137] Particularly preferred compounds of the invention will be asfollows:

[0138]N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

[0139] N-{4-[4-[(5methoxy-1H-indol-3-yl)methylcarbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

[0140](R)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

[0141](S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

[0142]N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamide;

[0143] or a salt of one of the latter, in particular a hydrochloride,dihydrochloride, fumarate or hemi-fumarate of one of the latter.

[0144] More particularly preferred compounds of the invention will be asfollows:

[0145]N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

[0146](R)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

[0147](S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide;

[0148] or a salt of one of the latter, in particular a hydrochloride,dihydrochloride, fumarate or hemi-fumarate of one of the latter.

[0149] The invention also offers useful new synthesis intermediates ofgeneral formula (Z)

[0150] in which:

[0151] A, X, Het, Y and R₆ have the same meaning as in general formula(I); and

[0152] W represents an amino or nitro radical;

[0153] with the exception however of3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-nitrophenyl)-benzamide.

[0154] The invention further comprises a process for preparing acompound of general formula (I) as defined earlier, characterized inthat a compound of general formula (Y)

[0155] in which:

[0156] A, X, Het, Y and R₆ have the same meaning as in general formula(I); and

[0157] W represents an amino radical;

[0158] is reacted in a lower alcohol, such as methanol, ethanol,isopropyl alcohol or t-butanol, preferably in isopropyl alcohol, at atemperature between 20 and 90° C., for example at 50° C., and for one to48 hours, preferably for 15 to 24 hours, optionally in the presence ofDMF, with a compound of general formula (IV)

[0159] said compound of general formula (IV) being optionally salifiedby a mineral acid G, B having the same meaning as in general formula (I)and L representing a leaving group and in particular an alkoxy,thioalkyl, sulphonic acid, halide, aryl alcohol or tosyl radical (otherleaving groups well known to a person skilled in the art which canoptionally be used for the invention are described in the followingwork: Advanced Organic Chemistry, J. March, 3rd Edition (1985), McGraw-Hill, p. 315). Preferably, G represents HCl, HBr or HI.

[0160] According to a particular variant of the invention, the compoundsof the invention correspond to general formula (I)_(L):

[0161] in which:

[0162] A represents:

[0163] either a

[0164] radical in which R₁ and R₂ represent, independently, a hydrogenatom, a halogen, the OH group, a linear or branched alkyl or alkoxyradical having from 1 to 6 carbon atoms,

[0165] R₃ represents a hydrogen atom, a linear or branched alkyl radicalhaving from 1 to 6 carbon atoms or a —COR₄ radical,

[0166] R₄ represents a linear or branched alkyl radical having from 1 to6 carbon atoms,

[0167] or a

[0168] radical in which R₃ has the meaning indicated above

[0169] or a

[0170] radical in which R₅ represents a hydrogen atom, the OH group or alinear or branched alkyl or alkoxy radical having from 1 to 6 carbonatoms;

[0171] B represents a linear or branched alkyl radical having from 1 to6 carbon atoms, carbocyclic or heterocyclic aryl with 5 or 6 memberscontaining from 1 to 4 heteroatoms chosen from O, S, N and in particularthe thiophene, furan, pyrrole or thiazole radicals, the aryl radicalbeing optionally substituted by one or more groups chosen from thelinear or branched alkyl, alkenyl or alkoxy radicals having from 1 to 6carbon atoms;

[0172] X represents -Z₁-, -Z₁-CO—, —CH═CH—CO—, -Z₁-NR₃—CO—, -Z₁-NR₃—CS—,-Z₁-NR₃—SO₂— or a single bond;

[0173] Y represents a radical chosen from the -Z₂-Q, piperazine,homopiperazine, 2-methylpiperazine, 2,5-dimethyl-piperazine,4-aminopiperidine, —NR₃-Z₂-Q-, —NR₃—CO-Z₂-Q-, —NR₃—NH—CO-Z₂-,—NH—NH-Z₂-, —NR₃—O-Z₂-, —NR₃—SO₂—NR₃-Z₂-, —O-Z₂-Q-, —O—CO-Z₂-Q- or—S-Z₂-Q- radicals,

[0174] in which Q represents a single bond, O-Z₃, R₃—N-Z₃ or S-Z₃;

[0175] Z₁, Z₂ and Z₃ represent independently a single bond or a linearor branched alkylene radical having from 1 to 6 carbon atoms;preferably, Z₁, Z₂ and Z₃ represent —(CH₂)_(m)—, m being an integercomprised between 0 and 6;

[0176] R₆ represents a hydrogen atom or an OH group;

[0177] or are salts of the latter.

[0178] There will generally be preferred the compounds of generalformula (I)_(L) for which:

[0179] X represents a linear or branched alkylene radical having from 1to 6 carbon atoms and Y represents a piperazine, homopiperazine,2-methylpiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine,—NR₃-Z₂-Q-, —NR₃—NH—CO-Z₂-, —NH—NH-Z₂- or —NR₃—O-Z₂- radical; or

[0180] X represents -Z₁-CO— or —CH═CH—CO— and Y represents a piperazine,homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine,4-aminopiperidine, —NR₃-Z₂-Q-, —NR₃—NH—CO-Z₂-, —NH—NH-Z₂-, —NR₃—O-Z₂-,—O-Z₂-Q- radical or —NR₃—CO-Q′-radical with Q′=R₃—N-Z₃; or

[0181] X represents -Z₁-NR₃—CO— and Y represents -Z₂-Q-, —NH-Z₂-Q-,—NH—CO-Z₂-Q″- with Q″=O-Z₃-, R₃—N-Z₃- or S-Z₃-, or Y represents—NR₃—SO₂—NR₃-Z₂- or —O-Z₂-Q-; or

[0182] X represents -Z₁-NH—CO— and Y represents a piperazine,homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine,4-aminopiperidine, —NR₃-Z₂-Q-, —NR₃—NH—CO-Z₂-, —NH—NH-Z₂- or —NR₃—O-Z₂-radical; or

[0183] X represents -Z₁-NR₃—SO₂— and Y represents -Z₂-Q″- with Q″=O-Z₃-,R₃—N-Z₃- or S-Z₃-, or Y represents —NR₃-Z₂-Q-; or

[0184] X represents -Z₁- and Y represents —O—CO-Z₂-Q-; or

[0185] X represents -Z₁-NR₃—CS— and Y represents —NH-Z₂-Q-, or apiperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethyl-piperazine,4-aminopiperidine, —NR₃-Z₂-Q-, —NH—NH-Z₂- or —NR₃—O-Z₂- radical; or

[0186] X represents a bond and Y represents —O-Z₂-NH—, —S-Z₂-NH—.

[0187] Moreover, the X-Y group will preferably be chosen from thefollowing radicals:

[0188] in which T represents a single bond, the —NR₃— radical or the—CO—NR₃— radical, or

[0189] or

[0190] in which R_(p) represents a hydrogen atom or a methyl radical, or

[0191] in which U represents a -Z₂, —NR₃—CO—, —CO-Z₂-O—, —CO—, —NR₃—radical or an oxygen atom, or

[0192] the Z₁, Z₂ and R₃ radicals having the meaning indicated above.

[0193] Finally, there will be particularly preferred for the inventionthe compounds of general formula (I)_(L) presenting the followingcharacteristics:

[0194] either:

[0195] A represents:

[0196] X represents —CO— or —NH—CO—;

[0197] and Y represents an —NH-Z₂-Q- or piperazine radical, Qrepresenting a single bond or an O-Z₃, R₃—N-Z₃ or S-Z₃ radical, and Z₂and Z₃ representing independently a bond or a linear or branchedalkylene radical having from 1 to 6 carbon atoms and R₃ represents ahydrogen atom or a linear or branched alkyl radical having from 1 to 6carbon atoms.

[0198] or: R₆ is an OH group.

[0199] The invention also offers, as new industrial products, thesynthetic intermediates of the products of general formula (I)_(L),namely the products of general formula (II)_(L):

[0200] in which:

[0201] W represents an amino or nitro radical,

[0202] A represents:

[0203] either a

[0204] radical in which R₁ and R₂ represent, independently, a hydrogenatom, a halogen, the OH group, a linear or branched alkyl or alkoxyradical having from 1 to 6 carbon atoms,

[0205] R₃ represents a hydrogen atom, a linear or branched alkyl radicalhaving from 1 to 6 carbon atoms or a —COR₄ radical,

[0206] R₄ representing a linear or branched alkyl radical having from 1to 6 carbon atoms,

[0207] or a

[0208] radical in which R₃ has the meaning indicated above

[0209] or a

[0210] radical in which R₅ represents a hydrogen atom, the OH group or alinear or branched alkyl or alkoxy radical having from 1 to 6 carbonatoms;

[0211] X represents -Z₁-, -Z₁-CO—, —CH═CH—CO—, -Z₁-NR₃—CO—, -Z₁-NR₃—CS—,-Z₁-NR₃—SO₂— or a single bond;

[0212] Y represents a radical chosen from the -Z₂-Q, piperazine,homopiperazine, 2-methylpiperazine, 2,5-dimethylpiperazine,4-aminopiperidine, —NR₃-Z₂-Q-, —NR₃—CO-Z₂-Q-, —NR₃—NH—CO-Z₂-,—NH—NH-Z₂-, —NR₃—O-Z₂-, —NR₃—SO₂—NR₃-Z₂-, —O-Z₂-Q-, —O—CO-Z₂-Q- or—S-Z₂-Q- radicals, in which Q represents a single bond, O-Z₃ R₃—N-Z₃ orS-Z₃;

[0213] Z₁, Z₂ and Z₃ represent independently a single bond or a linearor branched alkylene radical having from 1 to 6 carbon atoms;preferably, Z₁, Z₂ and Z₃ represent —(CH₂)_(m)—, m being an integercomprised between 0 and 6;

[0214] R₆ represents a hydrogen atom or an OH group;

[0215] with the exception however of3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-nitrophenyl)-benzamide;

[0216] or the salts of the latter.

[0217] Moreover, the invention offers in particular, as new industrialproducts, the following compounds, which are synthetic intermediates ofproducts of general formula (I):

[0218]3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide;

[0219]3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide;

[0220]3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-aminophenyl)methyl]-benzamide;

[0221] 4-acetoxy-3,5-dimethoxy-N-[(4-nitrophenyl)methyl]-benzamide;

[0222] 4-acetoxy-3,5-dimethoxy-N-[(4-aminophenyl)methyl]-benzamide;

[0223]3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide;

[0224]3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-aminophenyl)ethyl]-benzamide;

[0225] 4-acetoxy-3,5-dimethoxy-N-[2-(4-nitrophenyl)ethyl]-benzamide;

[0226] 4-acetoxy-3,5-dimethoxy-N-[2-(4-aminophenyl)ethyl]-benzamide;

[0227] 3,4,5-trihydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide;

[0228] 3,4,5-trihydroxy-N-[2-(4-aminophenyl)ethyl]-benzamide;

[0229]2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl)-phenol;

[0230]2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-aminophenyl)-1-piperazinyl]-carbonyl}-phenol;

[0231]2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-methyl}-phenol;

[0232]2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-aminophenyl)-1-piperazinyl]-methyl}-phenol;

[0233]2,6-dimethoxy-4-{[4-(4-nitrophenyl)-1-piperazinyl]carbonyl}-phenol;

[0234]2,6-dimethoxy-4-{[4-(4-aminophenyl)-1-piperazinyl]carbonyl}-phenol;

[0235]3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-nitrophenyl)-2H-1-benzopyran-2-carboxamide;

[0236]3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-aminophenyl)-2H-1-benzopyran-2-carboxamide;

[0237]3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;

[0238]3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;

[0239] 1-[(5methoxy-1H-indol-3-yl)methylcarbonyl]-4-(4-nitrophenyl)-piperazine;

[0240] 1-[(5methoxy-1H-indol-3-yl)methylcarbonyl]-4-(4-aminophenyl)-piperazine;

[0241]2,6-bis-(1,1-dimethylethyl)-4-{3-[4-(4-nitrophenyl)-1-piperazinyl]-3-oxo-2-propenyl}-phenol;

[0242]2,6-bis-(1,1-dimethylethyl)-4-{3-[4-(4-aminophenyl)-1-piperazinyl]-3-oxo-2-propenyl}-phenol;

[0243]3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-nitrophenyl)methyl]-benzamide;

[0244]3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-aminophenyl)methyl]-benzamide;

[0245]N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)methyl]-urea;

[0246]N-[(4-aminophenyl)methyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea;

[0247]3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-nitrophenyl)-2-propenamide;

[0248]3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-aminophenyl)-2-propenamide;

[0249]3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-nitrophenyl)-2-propenamide;

[0250]3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-aminophenyl)-2-propenamide;

[0251]5-{[4-(4-nitrophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triol;

[0252]5-{[4-(4-aminophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triol;

[0253]N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)carbonylamino]-urea;

[0254]N-[(4-aminophenyl)carbonylamino]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea;

[0255]N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)methyl]-thiourea;

[0256]N-[(4-aminophenyl)methyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-thiourea;

[0257]N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[2-(4-nitrophenyl)ethyl]-urea;

[0258]N-[2-(4-aminophenyl)ethyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea;

[0259]1-{[3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl]carbonyl}-4-(4-nitrophenyl)piperazine;

[0260]1-{[3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl]carbonyl}-4-(4-aminophenyl)piperazine;

[0261] hexahydro-4-(4-nitrophenyl)-1H-1,4-diazepine;

[0262]1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]hexahydro-4-(4-nitrophenyl)-1H-1,4-diazepine;

[0263]1-(4-aminophenyl)-4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]hexahydro-1H-1,4-diazepine;

[0264] hydrochloride duN-[4-{4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1H-1,4-diazepin-1-yl}phenyl]-2-thiophenecarboximidamidehydrochloride;

[0265](R)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;

[0266](R)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;

[0267](S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl1-2H-1-benzopyran-6-ol;

[0268](S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol;

[0269]3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(3-nitrophenyl)ethyl]-benzamide;

[0270]3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(3-aminophenyl)ethyl]-benzamide;

[0271] 2-(4-nitrophenyl)ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoate;

[0272] 2-(4-aminophenyl)ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate;

[0273] or their salts.

[0274] Finally, this particular variant of the invention also comprisesprocesses for the preparation of compounds of general formula (I)_(L) asdefined above and consisting, for example, of the reaction in a loweralcohol such as methanol, ethanol, isopropyl alcohol or t-butanol,preferably in isopropyl alcohol, at a temperature comprised between 20and 90° C., for example at 50° C., and for 1 to 48 hours, preferably for15 to 24 hours, optionally in the presence of DMF, of a compound ofgeneral formula (III)_(L) as defined above with a compound of generalformula (IV)_(L)

[0275] said compound of general formula (IV)_(L) being optionallysalified by a mineral acid G, B having the meaning indicated above and Lrepresenting a leaving group and in particular an alkoxy, thioalkyl,sulphonic acid, halide, aryl alcohol or tosyl radical (other leavinggroups well known to a person skilled in the art which can optionally beused for the invention are described in the following work: AdvancedOrganic Chemistry, J. March, 3rd Edition (1985), Mc Graw-Hill, p. 315).Preferably, G represents HCl, HBr or HI.

[0276] Other production processes can be envisaged and can be consultedin the literature (for example: The Chemistry of amidines and imidates,Vol. 2, Saul PATAI and Zvi RAPPOPORT, John Wiley & Sons, 1991).

[0277] According to another particular variant of the invention, thecompounds of the invention correspond to general formula (I)_(H):

[0278] in which:

[0279] A is a hydrogen atom or an aromatic corresponding to structures:

[0280] in which R₁ and R₂ represent, independently, a hydrogen atom, ahalogen, the OH group, a linear or branched alkyl radical having from 1to 6 carbon atoms, a linear or branched alkoxy radical having from 1 to6 carbon atoms R₃ represents a hydrogen atom, a linear or branched alkylradical having from 1 to 6 carbon atoms or a —COR₄ radical, R₄representing an alkyl radical having from 1 to 6 carbon atoms, or

[0281] B represents a linear or branched alkyl radical having from 1 to6 carbon atoms, phenyl, pyridinyl or a heterocycle with 5 memberscontaining from 1 to 4 heteroatoms chosen from O, S, N and moreparticularly: thiophene, furan, pyrrole or thiazole, the carbons ofwhich are optionally substituted by one or more groups chosen from alinear or branched alkyl radical having from 1 to 6 carbon atoms; analkoxy radical having from 1 to 6 carbon atoms or a halogen;

[0282] X represents —CO—N(R₃)—X′—, —NH—CO—X′—, —CH═, —CO— or a bond,

[0283] X′ representing —(CH₂)_(n)— with n an integer from 0 to 6;

[0284] Y represents —Y′—, —CO—NH—Y′, —Y′—NH—CO—, —CO—Y′—, —Y′—CO,—N(R₃)—Y′—, —Y′—N(R₃)—, Y′—CH₂—N(R₃)—CO—, -o-Y′—, —Y′—O—, —S—Y′—,—Y′—S—, —Y′—O—Y′—, —Y′—N(R₃)—Y′— or a bond, Y′ representing —(CH₂)_(n)—with n an integer from 0 to 6;

[0285] Het represents a heterocycle containing from 1 to 5 heteroatomschosen from O, N, S which can be substitued by one or more substituentsX′—OR₃, X′—NR₃, X′—S—R₃ and such as for example:

[0286] oxetane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene,tetrahydrothiophene, sulpholane, imidazole, imidazoline,dihydroimidazole-2-one, dihydroimidazole-2-thione, oxazole, isoxazole,oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole,thiazoline, thiazolidine, thiazolidinone, hydantoine, 1,2,4-triazole,1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxyde-1,2,5-thiadiazolidine,1,2,4-triazole-3-one, tetrazole, tetrahydropyridine,

[0287] with the exception of the following heterocycles: piperazines,homopiperazines, 4-aminopiperidine;

[0288] it being understood that when A represents a hydrogen atom, Hetdoes not represent a piperidine, pyrrolidine or morpholine radical.

[0289] The compounds of general formula (I)_(H) containing one or moreasymmetrical centres having isomer forms. The racemics and enantiomersof these compounds are also part of this invention. Similarly, thecompounds of the invention can also exist in the state of bases oraddition salts with acids.

[0290] More particularly the invention relates to the compounds ofgeneral formula (I)_(H) in which:

[0291] A is a hydrogen atom or an aromatic corresponding to thestructure:

[0292] in which:

[0293] R₁ and R₂ represent, independently a linear or branched alkylradical having 1 to 6 carbon atoms or a linear or branched alkoxyradical having from 1 to 6 carbon atoms,

[0294] R₃ represents a hydrogen atom or a linear or branched alkylradical having from 1 to 6 carbon atoms;

[0295] B represents a heterocycle with 5 members containing from 1 to 4heteroatoms chosen from O, S, N and more particularly: thiophene, furan,pyrrole or thiazole, the carbons of which are optionally substitued byone or more groups chosen from a linear or branched alkyl having from 1to 6 carbon atoms, an alkoxy radical having from 1 to 6 carbon atoms ora halogen;

[0296] X represents —NH—CO—X′—, —CH═, —CO— or a bond,

[0297] X′ representing —(CH₂)_(n)— with n an integer from 0 to 6;

[0298] Y represents —Y′—, —Y′—NH—CO—, —Y′—CO—, —Y′—O—, —Y′—O—Y′—,—Y′—N(R₃)—Y′— or a bond, Y′ representing —(CH₂)_(n)— with n an integerfrom 0 to 6;

[0299] Het represents a heterocycle containing from 1 to 5 heteroatomschosen from O, N, S which can be substituted by one or more substituentsX′—OR₃, X′—NR₃, X′—S—R₃ and such as for example:

[0300] oxetane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene,tetrahydrothiophene, sulpholane, imidazole, imidazoline,dihydroimidazole-2-one, dihydroimidazole-2-thione, oxazole, isoxazole,oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole,thiazoline, thiazolidine, thiazolidinone, hydantoin, 1,2,4-triazole,1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxyde-1,2,5-thiadiazolidine,1,2,4-triazole-3-one, tetrazole, tetrahydropyridine,

[0301] with the exception of the following heterocycles: piperazines,homopiperazines, 4-aminopiperidine.

[0302] Quite particularly the invention relates to the compounds ofgeneral formula (I)_(H) in which:

[0303] A is a hydrogen atom or an aromatic corresponding to thestructure:

[0304] in which:

[0305] R₁ and R₂ represent, independently a linear or branched alkylradical having from 1 to 6 carbon atoms or a linear or branched alkoxyradical having from 1 to 6 carbon atoms,

[0306] R₃ represents a hydrogen atom or a linear or branched alkylradical having from 1 to 6 carbon atoms;

[0307] B represents a thiophene ring, the carbons of which areoptionally substituted by one or more groups chosen from a linear orbranched alkyl having from 1 to 6 carbon atoms, an alkoxy radical havingfrom 1 to 6 carbon atoms or a halogen;

[0308] X represents —NH—CO—X′—, —CH═, —CO— or a bond,

[0309] X′ representing —(CH₂)_(n)— with n an integer from 0 to 6;

[0310] Y represents —Y′—, —Y′—NH—CO—, —Y′—CO—, —Y′—O—, —Y′—O—Y′—,—Y′—N(R₃)—Y′— or a bond, Y′ representing —(CH₂)_(n)— with n an integerfrom 0 to 6;

[0311] Het represents a heterocycle containing from 1 to 5 heteroatomschosen from O, N, S which can be substituted by one or more substituentsX′—OR₃, X′—NR₃, X′—S—R₃ and such as for example:

[0312] oxetane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene,tetrahydrothiophene, sulpholane, imidazole, imidazoline,dihydroimidazole-2-one, dihydroimidazole-2-thione, oxazole, isoxazole,oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole,thiazoline, thiazolidine, thiazolidinone, hydantoin, 1,2,4-triazole,1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxyde-1,2,5-thiadiazolidine,1,2,4-triazole-3-one, tetrazole, tetrahydropyridine,

[0313] with the exception of the following heterocycles: piperazines,homopiperazines, 4-aminopiperidine.

[0314] Preferred compounds for this variant of the invention include thefollowing compounds (described in the examples):

[0315] N-[4-(1H-imidazol-1-yl)phenyl]-2-thiophenecarboximidamide;

[0316] N-[4-(3-thiazolidinylmethyl)phenyl]-2-thiophenecarboximidamide;

[0317]N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamide;

[0318] N-[4-(1H-imidazol-1-yl methyl)phenyl]-2-thiophenecarboximidamide;

[0319]N-[4-{2-(3-thiazolidinyl)ethyl}phenyl]-2-thiophenecarboximidamide;

[0320]N-{4-[2-(1H-imidazol-1-yl)ethyl]phenyl}-2-thiophenecarboximidamide;

[0321]N-{4-[2-(1,2,3,6-tetrahydropyridin-1-yl)ethyl]phenyl}-2-thiophenecarboximidamide;

[0322]N-[4-(3-thiazolidinylcarbonylmethyl)phenyl]-2-thiophenecarboximidamide;

[0323]N-(4-{[2-thiazolidinyl]carbonylaminomethyl}phenyl)-2-thiophenecarboximidamide;

[0324]N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-[4-{imino(2-thienyl)-methylaminophenyl]-2-furan carboxamide;

[0325]3-(3,5-di-t-butyl-4-hydroxyphenyl)-1-[4-{imino(2-thienyl)-methylamino}phenyl]-2,5-imidazolidinedione;

[0326]2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-[4-{imino(2-thienyl)-methylamino}phenyl]-4-thiazolidinone;

[0327]5-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-[4-{imino(2-thienyl)methylamino}phenyl]-2,4-imidazolidinedione;

[0328]2-(S)-4-(S)-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)-phenyl]-4-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-prolinamide;

[0329]5,6-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1-(2H)-pyridinecarboxamide;

[0330]N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(R.S)-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-(R)-thiazolidinecarboxamide;

[0331]N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-thiazolecarboxamide;

[0332]N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy1-pyrrolidine-2-(R)-carboxamide;

[0333] methyl1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)carbonyl]-4-(S)-{4-[(imino(2-thienyl)methyl)amino]-phenoxy}-pyrrolidine-2-(S)-carboxylate;

[0334]1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine;

[0335]3-{[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]amino}-1-{4-[(imino(2-thienyl)methyl)amino]phenyl}pyrrolidine;

[0336]4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]benzoyl}-N-methyl-1H-imidazole-2-methanamine;

[0337]N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1H-pyrrole-2-carboxamide;

[0338]1-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-{[4-[[imino(2-thienyl)methyl]amino]phenyl]carbonyl}-2-imidazolidinone;

[0339]3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl1-5-isoxazoleacetamide;

[0340]4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2-thiazolemethanamine;

[0341]4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-1H-imidazole-2-methanamine;

[0342]3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-{2-{4-[(imino(2-thienyl)methyl)amino]phenoxy}ethyl}isoxazole;

[0343]1-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]amino}-carbonyl}-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidine;

[0344]1-(2-hydroxy-5-methoxybenzoyl)-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidine;

[0345]1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-4-[4-[(imino(2-thienyl)methyl)amino]phenoxy}-piperidine;

[0346]1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-{4-[(imino(2-thienyl)methyl)amino]-phenoxy}azetidine;

[0347] as well as their salts, in particular their hydrochlorides,dihydrochlorides, fumarates or hemi-fumarates.

[0348] Preferred compounds for this variant of the invention are thefollowing compounds:

[0349] N-[4-(1H-imidazol-1-yl)phenyl]-2-thiophenecarboximidamidehydroiodide;

[0350] N-[4-(3-thiazolidinylmethyl)phenyl]-2-thiophenecarboximidamide;

[0351]N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamidefumarate;

[0352] N-[4-(1H-imidazol-1-yl methyl)phenyl]-2-thiophenecarboximidamidehydrochloride;

[0353]N-[4-{2-(3-thiazolidinyl)ethyl}phenyl]-2-thiophenecarboximidamide;

[0354]N-{4-[2-(1H-imidazol-1-yl)ethyl]phenyl}-2-thiophenecarboximidamidehydroiodide;

[0355]N-{4-[2-(1,2,3,6-tetrahydropyridin-1-yl)ethyl]phenyl}-2-thiophenecarboximidamidefumarate

[0356]N-[4-(3-thiazolidinylcarbonylmethyl)phenyl]-2-thiophenecarboximidamide;

[0357]N-(4-{[2-thiazolidinyl]carbonylaminomethyl}phenyl)-2-thiophenecarboximidamidefumarate;

[0358]N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-[4-{imino(2-thienyl)-methylamino}phenyl]-2-furancarboxamide hydroiodide;

[0359]3-(3,5-di-t-butyl-4-hydroxyphenyl)-1-[4-{imino(2-thienyl)-methylamino}phenyl]-2,5-imidazolidinedionehydrochloride;

[0360]2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-[4-{imino(2-thienyl)-methylamino}phenyl]-4-thiazolidinonehydrochloride;

[0361]5-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-[4-{imino(2-thienyl)methylamino}phenyl]-2,4-imidazolidinedionefumarate;

[0362]2-(S)-4-(S)-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)-phenyl]-4-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-prolinamidehydrochloride;

[0363]5,6-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1-(2H)-pyridinecarboxamide hydrochloride;

[0364]N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(R,S)-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-(R)-thiazolidinecarboxamide fumarate;

[0365]N-[4-(4-phenyl-1,2,3,6-tetrahydropyridine-1-yl)phenyl]-2-thiophenecarboximidamidehydroiodide;

[0366]N-[4-hydroxy-3,5-bis-(1,1-dimethyl)ethyl-phenyl]-2-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-thiazolecarboxamide hydrochloride;

[0367] or their salts or enantiomers.

[0368]N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamideor its salts is the most preferred compound among the compounds of thisvariant of the invention.

[0369] Other preferred compounds include:

[0370]N-{4-[({[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}amino)methyl]phenyl}thiophene-2-carboximidamide;

[0371]N-{3-[({[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}amino)methyl]phenyl}thiophene-2-carboximidamide;

[0372]N-(4-{[{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}(methyl)amino]methyl}phenyl)thiophene-2-carboximidamide;

[0373] N-[3-({[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide;

[0374] N-(3-{[(3,5-di-tert-butyl-4-hydroxybenzyl)amino]methyl}phenyl)thiophene-2-carboximidamide;

[0375] N-[3-({[2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethyl]amino}methyl)phenyl]thiophene-2-carboximidamide;

[0376] N-[3-({[3-(4-hydroxy-3,5-diisopropylphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide;

[0377] N-(3-{[(4-hydroxy-3,5-diisopropylbenzyl)amino]methyl}phenyl)thiophene-2-carboximidamide;

[0378] N-[3-({[2-(4-hydroxy-3,5-diisopropylphenyl)ethyl]amino}methyl)phenyl]thiophene-2-carboximidamide;

[0379]N-2-(3,5-di-tert-butyl-4-hydroxybenzoyl)-N-1-(4-{[imino(thien-2-yl)methyl]amino}phenyl)-L-leucinamide;

[0380] and pharmaceutically acceptable salts thereof.

[0381] Among the latter compounds, the following are more preferred:

[0382] N-[3-({[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide;

[0383] N-[3-({[3-(4-hydroxy-3,5-diisopropylphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide;

[0384] N-[3-({[2-(4-hydroxy-3,5-diisopropylphenyl)ethyl]amino}methyl)phenyl]thiophene-2-carboximidamide;

[0385] and pharmaceutically acceptable salts thereof.

[0386] The invention also offers, as new industrial products, thesynthetic intermediates of the products of general formula (I)_(H),namely the products of general formula (II)_(H), (III)_(H), (V)_(H),(VI)_(H) and (VII)_(H)

[0387] in which

[0388] A is a hydrogen atom or an aromatic corresponding to structures:

[0389] in which:

[0390] R₁ and R₂ represent, independently, a hydrogen atom, a halogen,the OH group, a linear or branched alkyl radical having from 1 to 6carbon atoms, a linear or branched alkoxy radical having from 1 to 6carbon atoms,

[0391] R₃ represents a hydrogen atom, a linear or branched alkyl radicalhaving from 1 to 6 carbon atoms or a —COR₄ radical R₄ representing analkyl radical having from 1 to 6 carbon atoms, or

[0392] B represents a linear or branched alkyl radical having from 1 to6 carbon atoms, phenyl, pyridinyl or a heterocycle with 5 memberscontaining from 1 to 4 heteroatoms chosen from O, S, N and moreparticularly: thiophene, furan, pyrrole or thiazole, the carbons ofwhich are optionally substituted by one or more groups chosen from alinear or branched alkyl having from 1 to 6 carbon atoms, an alkoxyradical having from 1 to 6 carbon atoms or a halogen;

[0393] X represents —CO—N(R₃)—X′—, —NH—CO—X′—, —CH═, —CO— or a bond,

[0394] X′ representing —(CH₂)_(n)— with n an integer from 0 to 6;

[0395] Y represents —Y′—, —CO—NH—Y′, —Y′—NH—CO—, —CO—Y′—, —Y′—CO,—N(R₃)—Y′—, —Y′—N(R₃)—, Y′—CH₂—N(R₃)—CO—, —O—Y′—, —Y′—O—, —S—Y′—,—Y′—S—, —Y′—O—Y′—, —Y′—N(R₃)—Y′— or a bond, Y′ representing —(CH₂)_(n)—with n an integer from 0 to 6;

[0396] Het represents a heterocycle containing from 1 to 5 heteroatomschosen from O, N, S which can be substituted by one or more substituentsX′—OR₃, X′—NR₃, X′—S—R₃ and such as for example:

[0397] oxetane, pyrrole, pyrrolidine, furan, tetrahydrofuran, thiophene,tetrahydrothiophene, sulpholane, imidazole, imidazoline,dihydroimidazole-2-one, dihydroimidazole-2-thione, oxazole, isoxazole,oxazoline, isoxazoline, oxazolidine, oxazolidinone, thiazole,thiazoline, thiazolidine, thiazolidinone, hydantoin, 1,2,4-triazole,1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,1-dioxyde-1,2,5-thiadiazolidine,1,2,4-triazole-3-one, tetrazole, tetrahydropyridine,

[0398] with the exception of the following heterocycles: piperazines,homopiperazines, 4-aminopiperidine;

[0399] G_(p) represents a protective group of the amine functionpreferably cleavable in an anhydrous acid medium, such as for examplethe carbamates of t-butyl, trichloroethyl or trimethylsilylethyl or alsothe trityl group.

[0400] Finally, the invention offers preparation processes for thecompounds of general formula (I)_(H) as defined above and consisting of,for example, the reaction in a lower alcohol, such as methanol, ethanol,isopropyl alcohol or t-butanol, preferably in isopropyl alcohol, at atemperature between 20 and 90° C., for example at 50° C., and for one to48 hours, preferably for 15 to 24 hours, optionally in the presence ofDMF, of a compound of general formula (III)_(H)

[0401] with a compound of general formula (IV)_(H)

[0402] said compound of general formula (IV)_(H) optionally being ableto be salified by a mineral acid G, B having the meaning indicated aboveand L representing a parting group and in particular an alkoxy,thioalkyl, sulphonic acid, halide, aryl alcohol or tosyl radical (otherparting groups well-known to a person skilled in the art and beingoptionally able to be used for the invention are decribed in thefollowing work: Advanced Organic Chemistry, J. March, 3rd Edition(1985), Mc Graw-Hill, p. 315). Preferably, G represents HCl, HBr or HI.

[0403] A subject of the invention is also, as medicaments, the compoundsof general formula (I), (I)_(L) or (I)_(H) described previously or theirpharmaceutically acceptable salts. It also relates to pharmaceuticalcompositions containing these compounds or their pharmaceuticallyacceptable salts, and the use of these compounds or of theirpharmaceutically acceptable salts for producing medicaments intended toinhibit neuronal NO synthase or inductible NO synthase, to inhibitlipidic peroxidation or to provide the double function of NO synthaseinhibition and lipidic peroxidation.

[0404] More preferably,(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamideor a pharmaceutically acceptable salt thereof, will be used in thepharmaceutical compositions of the invention. The same will also bepreferred for producing medicaments according to the invention.

[0405] Other preferred compounds as active ingredients of pharmaceuticalcompositions according to the invention include:

[0406]N-{4-[({[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl)methyl}amino)methyl]phenyl}thiophene-2-carboximidamide;

[0407]N-{3-[({[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}amino)methyl]phenyl}thiophene-2-carboximidamide;

[0408]N-(4-{[{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}(methyl)amino]methyl}phenyl)thiophene-2-carboximidamide;

[0409] N-[3-({[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide;

[0410] N-(3-{[(3,5-di-tert-butyl-4-hydroxybenzyl)amino]methyl}phenyl)thiophene-2-carboximidamide;

[0411] N-[3-({[2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethyl]amino}methyl)phenyl]thiophene-2-carboximidamide;

[0412] N-[3-({[3-(4-hydroxy-3,5-diisopropylphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide;

[0413] N-(3-{[(4-hydroxy-3,5-diisopropylbenzyl)amino]methyl}phenyl)thiophene-2-carboximidamide;

[0414] N-[3-({[2-(4-hydroxy-3,5-diisopropylphenyl)ethyl]amino}methyl)phenyl]thiophene-2-carboximidamide;

[0415]N-2-(3,5-di-tert-butyl-4-hydroxybenzoyl)-N-1-(4-{[imino(thien-2-yl)methyl]amino}phenyl)-L-leucinamide;

[0416] and pharmaceutically acceptable salts thereof.

[0417] Among the latter compounds, the following are more preferred asactive ingredients of pharmaceutical compositions:

[0418] N-[3-({[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide;

[0419] N-[3-({[3-(4-hydroxy-3,5-diisopropylphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide;

[0420] N-[3-({[2-(4-hydroxy-3,5-diisopropylphenyl)ethyl]amino}methyl)phenyl]thiophene-2-carboximidamide;

[0421] and pharmaceutically acceptable salts thereof.

[0422] In a preferred manner, the compounds of general formula (I),(I)_(L) or (I)_(H), or their pharmaceutically acceptable salts, and inparticular(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamideor a pharmaceutically acceptable salt thereof, will be used produce amedicament intended to treat stroke, neurodegenerative diseases orischemic or hemorragic cardiac or cerebral infarctions, notably thoserelated with complications of coronary artery bypass grafting.

[0423] The invention therefore provides a method of treating stroke orneurodegenerative diseases comprising administering to said warm-bloodedanimal a compound of general formula (I), (I)_(L) or (I)_(H), or apharmaceutically acceptable salt thereof, and in particular(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamideor a pharmaceutically acceptable salt thereof, in an amount sufficientto inhibit stroke or neurodegenerative diseases.

[0424] The invention also provides a method of preventing or treatingischemic or hemorragic cardiac or cerebral infarctions related withcomplications of coronary artery bypass grafting in a warm-bloodedanimal comprising administering to said warm-blooded animal a compoundof general formula (I), (I)_(L) or (I)_(H), or a pharmaceuticallyacceptable salt thereof, and in particular(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamideor a pharmaceutically acceptable salt thereof, in an amount sufficientto inhibit said ischemic or hemorragic cardiac or cerebral infarctions.

[0425] For the methods of treatment described above, one can also use acompound selected from the following compounds:

[0426]N-{4-[({[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}amino)methyl]phenyl)thiophene-2-carboximidamide;

[0427]N-{3-[({[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}amino)methyl]phenyl}thiophene-2-carboximidamide;

[0428]N-(4-{[{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}(methyl)amino]methyl}phenyl)thiophene-2-carboximidamide;

[0429] N-[3-({[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide;

[0430] N-(3-{[(3,5-di-tert-butyl-4-hydroxybenzyl)amino]methyl}phenyl)thiophene-2-carboximidamide;

[0431] N-[3-({[2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethyl]amino}methyl)phenyl]thiophene-2-carboximidamide;

[0432] N-[3-({[3-(4-hydroxy-3,5-diisopropylphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide;

[0433] N-(3-{[(4-hydroxy-3,5-diisopropylbenzyl)amino]methyl}phenyl)thiophene-2-carboximidamide;

[0434] N-[3-({[2-(4-hydroxy-3,5-diisopropylphenyl)ethyl]amino}methyl)phenyl]thiophene-2-carboximidamide;

[0435]N-2-(3,5-di-tert-butyl-4-hydroxybenzoyl)-N-1-(4-{[imino(thien-2-yl)methyl]amino}phenyl)-L-leucinamide;

[0436] and pharmaceutically acceptable salts thereof.

[0437] Among the latter compounds, the following are more preferred forcarrying out the methods of treatment according to the invention:

[0438] N-[3-({[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide;

[0439] N-[3-({[3-(4-hydroxy-3,5-diisopropylphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide;

[0440] N-[3-({[2-(4-hydroxy-3,5-diisopropylphenyl)ethyl]amino}methyl)phenyl]thiophene-2-carboximidamide;

[0441] and pharmaceutically acceptable salts thereof.

[0442] By pharmaceutically acceptable salt is meant in particularaddition salts of inorganic acids such as hydrochloride, sulphate,phosphate, diphosphate, hydrobromide and nitrate, or of organic acids,such as acetate, maleate, fumarate, tartrate, succinate, citrate,lactate, methane sulphonate, p-toluenesulphonate, pamoate, oxalate andstearate. The salts formed from bases such as sodium or potassiumhydroxide also fall within the scope of the present invention, when theycan be used. For other examples of pharmaceutically acceptable salts,reference can be made to “Pharmaceutical salts”, J. Pharmi. Sci.66:1(1977).

[0443] The pharmaceutical composition can be in the form of a solid, forexample powders, granules, tablets, capsules, liposomes orsuppositories. Appropriate solid supports can be for example calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine and wax.

[0444] The pharmaceutical compositions containing a compound of theinvention can also be presented in the form of a liquid, for example,solutions, emulsions, suspensions or syrups. Appropriate liquid supportscan be, for example, water, organic solvents such as glycerol or theglycols, as well as their mixtures, in varying proportions, in water.

[0445] A medicament according to the invention can be administered bytopical, oral or parenteral route, by intramuscular injection, etc.

[0446] The envisaged administration dose for the medicament according tothe invention is comprised between 0.1 mg and 10 g according to the typeof active compound used.

[0447] According to the invention, the compounds of general formula(I)_(L) can be prepared by the process described below.

[0448] Preparation of Compounds of General Formula (I)

[0449] The preparation of the compounds of general formula (I),corresponding to subformulae (I)_(L) and (I)_(H), is describedhereafter.

[0450] A) Preparation of Compounds of General Formula (I)_(L):

[0451] The compounds of general formula (I)_(L) can be prepared fromintermediates of general formula (II)_(L) according to diagram 1.

[0452] The reduction of the nitro function of the intermediates ofgeneral formula (II)_(L) is generally carried out by catalytichydrogenation in ethanol, in the presence of Pd/C, except whenX=—CH═CH—CO— or Y=—O—CH₂—, the nitro group is selectively reduced using,for example, SnCl₂ (J. Heterocyclic Chem. (1987), 24, 927-930;Tetrahedron Letters (1984), 25, (8), 839-842). The reaction is thencarried out by heating the mixture to approx. 70° C., for at least threehours, in ethyl acetate, sometimes with added ethanol.

[0453] The aniline derivatives of general formula (III)_(L) thusobtained can be condensed on derivatives of general formula (IV)_(L),for example derivatives of O-alkyl thioimidate or S-alkyl thioimidatetype, in order to produce final compounds of general formula (I)_(L)(cf. diagram 1). For example, for B=thiophene, the derivatives ofgeneral formula (III)_(L) can be condensed on S-methylthiophenethiocarboxamide hydriodide, prepared according to a method in theliterature (Ann. Chim. (1962), 7, 303-337). Condensation can be carriedout by heating in an alcohol (for example in methanol or isopropanol),optionally in the presence of DMF at a temperature comprised between 50and 100° C. for a duration generally comprised between a few hours andovernight.

[0454] Preparation of Intermediates of General Formula (II)_(L):

[0455] The intermediates of general formula (II)_(L) can be prepared bydifferent processes depending on the chemical functions which are setup: amines, carboxamides, ureas, thioureas, sulphonamides,aminosulphonylureas, sulphamides, carbamates, ethers, esters,thioethers, acylureas, etc.:

[0456] When:

[0457] X=linear or branched alkylene radical having from 1 to 6 carbonatoms

[0458] and Y=piperazine, homopiperazine, 2-methylpiperazine,2,5-dimethylpiperazine, 4-aminopiperidine, —NR₃-Z₂-Q-, —NR₃—NH—CO-Z₂-,—NH—NH-Z₂-, —NR₃—O-Z₂-

[0459] The amines of general formula (II)_(L), diagram 2, in which A, X,Y and R₆ are as defined above, can be obtained by nucleophilesubstitution of the halogenated derivatives of general formula (VI)_(L)by an amine of general formula (VII)_(L). The reaction is carried out,for example, in DMF in the presence of K₂CO₃ at 20° C. The halogenatedderivatives of general formula (VI)_(L) can be accessed, for example, bybromation of the primary alcohols of general formula (V)_(L) using PBr₃,at 0° C., in anhydrous THF. The alcohols of general formula (V)_(L)which are not commercially available can be prepared according tomethods described in the literature (Tetrahedron Lett. (1983), 24, (24),2495-2496).

[0460] The amines of general formula (VII)_(L) in which Y representshomopiperazine, 2,5-dimethylpiperazine, 4-aminopiperidine or moregenerally —NR₃-Z₂-NR₃— are synthesized in three stages from thecorresponding commercial diamines. The diamines are selectivelymono-protected in the form of the carbamate (Synthesis (1984), (12),1032-1033; Synth. Commun. (1990), 20, (16), 2559-2564) before reactionby nucleophile substitution on a fluoronitrobenzene, in particular4-fluoronitrobenzene. The amines, previously protected, are released atthe last stage, according to methods described in the literature (T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, SecondEdition (Wiley-Interscience, 1991)), in order to produce intermediatesof general formula (VII)_(L).

[0461] When:

[0462] X=-Z₁-CO—, —CH═CH—CO—

[0463] and Y=piperazine, homopiperazine, 2-methylpiperazine,2,5-dimethylpiperazine, 4-aminopiperidine, —NR₃-Z₂-Q-, —NR₃—NH—CO-Z₂-,—NH—NH-Z₂-, —NR₃—O-Z₂-

[0464] The carboxamides of general formula (II)_(L), diagram 3, in whichA, X, Y and R₆ are as defined above, are prepared by condensation of thecommercial carboxylic acids of general formula (VIII)_(L) for X=-Z₁-CO—and of general formula (IX)_(L) for X=—CH═CH—CO— with amines of generalformula (VII)_(L). The non commercial acids can be synthesized accordingto methods similar to those described in the literature (J. Org. Chem.(1974), 39 (2), 219-222; J. Amer. Chem. Soc. (1957), 79, 5019-5023, andCHIMIA (1991), 45 (4), 121-123 when A represents a6-alkoxy-2,5,7,8-tetramethylchromane radical). The amines of generalformula (VII)_(L) in which Y represents homopiperazine,2,5-dimethylpiperazine, 4-aminopiperidine, or more generally—NR₃-Z₂-NR₃— are prepared according to methods similar to thosedescribed in the previous paragraph. The carboxamide bonds are formedunder standard conditions for peptide synthesis (M. Bodanszky and A.Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag,1984)) in THF, dichloromethane or DMF in the presence of a couplingreagent such as dicyclohexylcarbodiimide (DCC), 1.1′-carbonyldiimidazole(CDI) (J. Med. Chem. (1992), 35 (23), 4464-4472) or1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC orWSCI) (John Jones, The chemical synthesis of peptides, 54 (ClarendonPress, Oxford, 1991)).

[0465] When:

[0466] X=-Z₁-NR₃—CO—

[0467] and Y=-Z₂-Q-

[0468] The carboxamides of general formula (II)_(L) in which A, X, Y andR₆ are as defined above can also be prepared, as in diagram 4, bypeptide condensation of an amine of general formula (X) with acommercial acid of general formula (XI)_(L). When X=—NR₃—CO— and R₃═H,the compounds of general formula (X)_(L) are anilines which are obtainedby hydrogenation, in the presence of a catalytic quantity of Pd/C, thecorresponding nitrobenzene derivatives, themselves synthesized accordingto a method described in the literature (J. Org. Chem. (1968), 33 (1),223-226). When X.—NR₃—CO— and R₃ is a linear or branched alkyl radicalhaving from 1 to 6 carbon atoms, the monoalkylamines can be obtainedaccording to a process described in the literature (U.S. Pat. Nos.3,208,859 and 2,962,531). The non-commercial carboxylic acids of generalformula (XI)_(L) can be accessed using methods described in theliterature (Acta Chem. Scand. (1983), 37, 911-916; Synth. Commun.(1986), 16 (4), 479-483; Phophorus, Sulphur Silicon Relat. Elem. (1991),62, 269-273).

[0469] When:

[0470] X=-Z₁-NR₃—CO—

[0471] and Y=—NH-Z₂-Q-, —NH—CO-Z₂-Q- with Q=O-Z₃-, R₃—N-Z₃- or S-Z₃-,

[0472] The ureas of general formula (II)_(L), diagram 5, in which A, X,Y and R₆ are as defined above, are prepared by the addition of an amineof general formula (X)_(L) on an isocyanate of general formula(XII)_(L), (XIII)_(L) or (XIV)_(L) in a solvent such as chloroform at20° C. Synthesis of non-commercial isocyanates of general formula(XII)_(L) is described in the literature (J. Med. Chem. (1992), 35 (21),3745-3754). The halogenated intermediate ureas (XV)_(L) and (XVII)_(L)are then substituted by a derivative of general formula (XVI)_(L), inwhich Q represents O-Z₃-, R₃—N-Z₃- or S-Z₃-, in the presence of a basesuch as, for example, K₂CO₃ or NaH in an aprotic solvent such as THF orDMF in order to finally obtain ureas of general formula (II)_(L).

[0473] When:

[0474] X=-Z₁-NH—CO—

[0475] and Y=piperazine, homopiperazine, 2-methylpiperazine,2,5-dimethylpiperazine, 4-aminopiperidine, —NR₃-Z₂-Q-, —NR₃—NH—CO-Z₂-,—NH—NH-Z₂-, —NR₃—O-Z₂-

[0476] The ureas of general formula (II)_(L), diagram 6, in which A, X,Y and R₆ are as defined above, are prepared by the addition of an amineof general formula (VII)_(L), described previously, onto an isocyanateof general formula (XVIII)_(L) in the presence of a base such asdiisopropylethylamine.

[0477] The isocyanates of general formula (XVIII)_(L) are synthesizedfrom primary amines of general formula (X)_(L), described previously,triphosgene and a tertiary amine (J. Org. Chem. (1994), 59 (7),1937-1938).

[0478] The amines of general formula (VII)_(L) in which Y.—NH—O— areprepared according to a method described in the literature (J. Org.Chem. (1984), 49 (8), 1348-1352).

[0479] When:

[0480] X=-Z₁-NR₃—CO—

[0481] and Y=—NR₃—SO₂—NR₃-Z₂-

[0482] The aminosulphonylureas of general formula (II)_(L), diagram 7,in which A, X, Y and R₆ are as defined above, are prepared by theaddition of amines of general formula (X)_(L), described previously,onto chlorosulphonylisocyanate (J. Med. Chem. (1996), 39 (6),1243-1252). The intermediate chlorosulphonylurea (XIX)_(L) is thencondensed on the amines of general formula (VII)_(L), describedpreviously, in order to produce the aminosulphonylureas of generalformula (II)_(L) which can optionally be alkylated by a halogenatedderivative in the presence of a base such as, for example, NaH in orderto produce other derivatives of general formula (II)_(L).

[0483] When:

[0484] X=-Z₁-NR₃—SO₂—

[0485] and Y=-Z₂-Q-, with Q=O-Z₃-, R₃—N-Z₃- or S-Z₃-,

[0486] The sulphonamides of general formula (II)_(L) diagram 8, in whichA, X, Y and R₆ are as defined above, are prepared by the addition ofamines of general formula (X)_(L), described previously, ontohalogenoalkylsulphonyl chlorides of general formula (XX)_(L). Thehalogenoalkylsulphonamides of general formula (XXI)_(L), obtainedintermediately, are then condensed on an alcohol, an amine or a thiol ofgeneral formula (XVI)_(L) in the presence of a base such as, forexample, K₂CO₃ or NaH, in a polar solvent such as, for example,acetonitrile or DMF.

[0487] When:

[0488] X=-Z₁-NR₃—SO₂—

[0489] and Y=—NR₃-Z₂-Q-

[0490] The sulphamides of general formula (II)_(L), diagram 9, in whichA, X, Y and R₆ are as defined above are prepared in three stages fromamines of general formula (X)_(L) and chlorosulphonylisocyanate. Thereaction of an alcohol, such as tBuOH, on the isocyanate function ofchlorosulphonylisocyanate (Tetrahedron Lett. (1991), 32 (45), 6545-6546)leads to an intermediate of chlorosulphonylcarbamate type, which reactsin the presence of an amine of general formula (X)_(L) to produce aderivative of carboxylsulphamide type of general formula (XXII)_(L). Thetreatment of this intermediate in a strong acid medium produces thesulphamide derivative of general formula (XXIII)_(L). Alkylation of thecompounds of general formula (XXIII)_(L) by the halogenated derivativesof general formula (XXIV)_(L) in the presence of a base such as, forexample, NaH in a polar aprotic solvent allows sulphamide derivatives ofgeneral formula (II)_(L) to be obtained.

[0491] When:

[0492] X=-Z₁-NR₃—CO—

[0493] and Y=—O-Z₂-Q-

[0494] The carbamates of general formula (II)_(L), diagram 10, in whichA, X, Y and R₆ are as defined above, are prepared by the reaction ofamines of general formula (X)_(L), described previously, withchloroformate derivatives of general formula (XXV)_(L) preparedaccording to a method described in the literature (Tetrahedron Lett.(1993), 34 (44), 7129-7132).

[0495] When:

[0496] X=-Z₁-CO—, —CH═CH—CO—

[0497] and Y=—O-Z₂-Q-

[0498] The esters of general formula (II)_(L), diagram 11, in which A,X, Y and R₆ are as defined above, are prepared by the reaction of acidsof general formula (VIII)_(L) or (IX)_(L) and alcohols of generalformula (XXVI)_(L) in the presence de dicyclohexylcarbodiimide and of acatalytic quantity of 4-dimethylaminopyridine in a solvent such as, forexample, THF or DMF at 20° C.

[0499] When:

[0500] X=-Z₁-

[0501] and Y=—O—CO-Z₂-Q-

[0502] The esters of general formula (II)_(L), diagram 12, in which A,X, Y and R₆ are as defined above, can also be prepared by the reactionof acids of general formula (XI)_(L), described previously, with thealcohols of general formula (V)_(L) under the conditions describedpreviously.

[0503] When:

[0504] X=-Z₁-NR₃—CS—

[0505] and Y=—NH-Z₂-Q-, piperazine, homopiperazine, 2-methylpiperazine,2,5-dimethylpiperazine, 4-aminopiperidine, —NR₃-Z₂-Q-, —NH—NH-Z₂-,—NR₃—O-Z₂-

[0506] The thioureas of general formula (II)_(L) in which A, X, Y and R₆are as defined above, are prepared from the ureas described previouslyusing Lawesson's reagent, following an experimental protocol describedin the literature (J. Med. Chem. (1995), 38 (18), 3558-3565).

[0507] When:

[0508] X represents a bond

[0509] Y=—O-Z₂-Q-, —S-Z₂-Q-

[0510] and Q=-HN-

[0511] The etheroxides or thioetheroxides of general formula (II)_(L),diagram 13, in which A, X, Y and R₆ are as defined above are preparedfrom dihydroquinones of general formula (XXVII)_(L) (J. Chem. Soc.,Perkin Trans. I, (1981), 303-306) or thiophenols of general formula(XXVIII)_(L) (Bio. Med. Chem. Letters, (1993), 3 (12), 2827-2830) and anelectrophile (E⁺) such as, for example, bromoacetonitrile or4-nitrophenyloxazolinone, in the presence of K₂CO₃ (J. HeterocyclicChem., (1994), 31, 1439-1443). The nitriles must be reduced (lithiumhydride or catalytic hydrogenation) in order to produce intermediates ofgeneral formula (XXIX)_(L) or (XXX)_(L). The opening of thenitrophenyloxazolinones, accessible by reaction of the correspondingnitroanilines with chloroethylchloroformate as described in theliterature (J. Am. Chem. Soc.,(1953), 75, 4596), by phenols orthiophenols leads directly to compounds of general formula (XXIX)_(L) or(XXX)_(L) which are then condensed on fluoronitrobenzene in order toproduce intermediates of general formula (II)_(L).

[0512] When:

[0513] X represents -Z₁-CO— or —CH═CH—CO—Y=-NR₃—CO-Q-

[0514] and Q=R₃—N-Z₃

[0515] The acylureas of general formula (II)_(L), diagram 14, in whichA, X, Y and R₆ are as defined above are prepared by condensation ofacids of general formula (VIII)_(L) or (IX)_(L), diagram 3, and ureas ofgeneral formula (XXXI)_(L) in the presence of a coupling agent usuallyused in peptide synthesis, as described previously, in a solvent suchas, for example, dichloromethane or DMF. The ureas of general formula(XXXI)_(L) are accessible from isocyanates of general formula (XII)_(L),diagram 5, according to a method in the literature (J. Chem. Soc.,Perkin Trans. 1, (1985), (1), 75-79).

[0516] B) Preparation of Compounds of General Formula (I)_(H):

[0517] The compounds of general formula (I)_(H) can be prepared startingfrom intermediates of general formula (II)_(H), (III)_(H) or (V)_(H)according to diagram 15.

[0518] The reduction of the nitro function of the intermediates ofgeneral formula (II)_(H) is generally carried out by catalytichydrogenation in ethanol, in the presence of Pd/C, except when themolecules contain an unsaturation or a sulphur atom, this being a poisonto the Pd/C. In this case, the nitro group is selectively reduced, forexample, by heating the product in solution in ethyl acetate with alittle ethanol in the presence of SnCl₂ (J. Heterocyclic Chem. (1987),24, 927-930; Tetrahedron Letters (1984), 25, (8), 839-842) or by usingRaney Ni with hydrazine hydrate added to it (Monatshefte für Chemie,(1995), 126, 725-732).

[0519] The aniline derivatives of general formula (III)_(H) thusobtained can be condensed on derivatives of general formula (IV)_(H),for example derivatives of O-alkyl thioimidate or S-alkyl thioimidatetype, in order to produce final compounds of general formula (I)_(H)(cf. diagram 15). For example, for B=thiophene, the derivatives ofgeneral formula (III)_(H) can be condensed on S-methylethiophenethiocarboxamide hydriodide, prepared according to a method in theliterature (Ann. Chim. (1962), 7, 303-337). Condensation can be carriedout by heating in an alcohol (for example in methanol or isopropanol),optionally in the presence of DMF at a temperature comprised between 50and 100° C. for a duration generally comprised between a few hours andovernight.

[0520] The final molecules of general formula (I)_(H) are alsoaccessible through another synthetic route passing through theintermediates of general formula (V)_(H) which carry a heterocyclicamine function protected by a protective group “G_(p)”, for example a2-(trimethylsilyl)ethoxymethyl group (SEM) or by another protectivegroup mentioned in: Protective groups in organic synthesis, 2d ed.,(John Wiley & Sons Inc., 1991). The reduction and condensation stageswhich lead to intermediates (VI)_(H) and (VII)_(H) respectively arecarried out under the same conditions as those described previously. Thelast stage of the synthesis consists in regenerating, for example in anacid medium or in the presence of a fluoride ion, the protectedheterocyclic amine function. Alternatively, the intermediates of generalformula (V)_(H) can be converted directly into the intermediate ofgeneral formula (II)_(H) by release of the heterocyclic amine bytreatment, for example, in an acid medium or in the presence of afluoride ion.

[0521] Preparation of the Compounds of General Formula (II)_(H),(III)_(H) and (V)_(H):

[0522] The intermediates of general formula (II)_(H), (III)_(H) and(V)_(H) can be prepared by the different synthetic routes illustratedbelow.

[0523] When:

[0524] Het=Imidazole, tetrahydropyridine, thiazolidine,dihydroimidazole-2-one

[0525] and Y=—Y′—.

[0526] The amines of general formula (II)_(H), diagram 16, in which A,X, Y and Het are as defined above, can be obtained by nucleophilicsubstitution of commercial halogenated derivatives of general formula(IX)_(H) by a heterocyclic amine of general formula (VIII)_(H). Thereaction is carried out in acetonitrile, THF or DMF in the presence of abase such as K₂CO₃ at a temperature varying from 20 to 110° C. Thesynthesis of heterocyclic derivatives of general formula (VIII)_(H),which are not commercially-available, is described below.

[0527] When:

[0528] Het=imidazole, thiazolidine, tetrahydropyridine

[0529] and Y=—Y′—.

[0530] The heterocyclic amines of general formula (III)_(H), diagram 17,in which A, X, Y and Het are as defined above, are prepared in twostages starting from the amines of general formula (VIII)_(H) (seebelow). The mixture of a brominated derivative of general formula(X)_(H), the synthesis of which is explained in detail below, with anamine of general formula (VIII)_(H) in a solvent such as acetonitrile orDMF in the presence of a base leads to intermediates of general formula(XI)_(H). The deprotection of the amine function, in an organic acidmedium, allows the compounds of general formula (III)_(H) to beobtained.

[0531] When:

[0532] Het=thiazolidine

[0533] and Y=—CO—Y′—.

[0534] The carboxamides of general formula (III)_(H), diagram 18, inwhich A, X, Y and Het are as defined above, are prepared by condensationof the amines of general formula (VIII)_(H), decribed previously, withthe carboxylic acids of general formula (X.2)_(H). The carboxamide bondsare formed under standard conditions of peptide synthesis (M. Bodanszkyand A. Bodanszky, The Practice of Peptide Synthesis, 145(Springer-Verlag, 1984)) in THF, dichloromethane or DMF in the presenceof a coupling reagent such as dicyclohexylcarbodiimide (DCC),1,1′-carbonyldiimidazole (CDI) (J. Med. Chem. (1992), 35 (23),4464-4472) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (EDC or WSCI) (John Jones, The chemical synthesis ofpeptides, 54 (Clarendon Press, Oxford, 1991)). The synthesis of thecarboxylic acids of general formula (X.2)_(H) is described below. Theintermediates of general formula (XII)_(H) are then deprotected in anacid medium using, for example, trifluroroacetic acid or an organicsolution of HCl.

[0535] When:

[0536] Het=thiazolidine

[0537] and Y=—CO—NH—Y′—.

[0538] The carboxamides of general formula (V)_(H), diagram 19, in whichA, X, Y and Het are as defined above, are prepared by condensation ofcarboxylic acids of general formula (XIII)_(H) with the commercialamines of general formula (XIV)_(H) under standard conditions forpeptide synthesis. The synthesis of the carboxylic acids of generalformula (XIII)_(H) is described below.

[0539] When:

[0540] Het=thiazole, furan, pyrrole, tetrahydropyridine, pyrrolidine

[0541] and X=—NH—CO—X′—.

[0542] The carboxamides of general formula (IT)_(H), diagram 20, inwhich A, X, Y and Het are as defined above, are prepared by condensationof anilines of general formula (XV)_(H) with the carboxylic acids ofgeneral formula (XVI)_(H) under standard conditions for peptidecondensation. The anilines of general formula (XV)_(H) are obtained byhydrogenation, in the presence of a catalytic quantity of Pd/C, ofcorresponding nitrobenzene derivatives, themselves synthesized accordingto a method described in the literature (J. Org. Chem. (1968), 33 (1),223-226). The acids of general formula (XVI)_(H), diagram 20, which arenot commercially available, are prepared according to methods describedin the literature.

[0543] The synthesis of pyrroles is described in Chem. Heterocycl.Compd., 1982, 18, 375. The substitued prolines are accessible startingfrom commercial hydroxyprolines and are prepared according to methodsdescribed in J. Org. Chem., 1991, 56, 3009.

[0544] The synthesis of the thiazole and tetrahydropyridine derivativesis described below.

[0545] When:

[0546] Het=hydantoin

[0547] and Y=—Y′—.

[0548] The hydantoins of general formula (II)_(H), diagram 21, in whichA, X, Y and Het are as defined above, are prepared in 3 stages startingfrom the anilines of general formula (XV)_(H) described previously. Thesubstitution of the aniline by ethyl bromoacetate is carried out in thepresence of sodium acetate in ethanol at a temperature of approximately60-70° C. The monosubstitution product of general formula (XVII)_(H) isthen condensed on an isocyanate of general formula (XVIII)_(H) in anorganic solvent such as, for example, dichloromethane, at a temperatureof approximately 20° C. The cyclization of urea (XIX)_(H) is carried outby heating, at 50° C., in ethanol, according to an experimental protocoldescribed in the literature (J. Heterocyclic Chem., (1979), 16,607-608). The isocyanates of general formula (XVIII)_(H) are synthesisedstarting from the corresponding commercial primary amines, triphosgeneand a tertiary amine (J. Org. Chem. (1994), 59 (7), 1937-1938).

[0549] When:

[0550] Het=thiazolidinone

[0551] and Y=—Y′—.

[0552] The thiazolidinones of general formula (II)_(H), diagram 22, inwhich A, X, Y and Het are as defined above, are prepared starting fromcommercial amines of general formula (XIV)_(H) and aldehydes of generalformula (XX)_(H) in the presence of mercaptoacetic acid according to anexperimental protocol described in the literature (J. Med. Chem.,(1992), 35, 2910-2912).

[0553] When:

[0554] Het=hydantoin

[0555] X=—CH═ and Y=—Y′—.

[0556] The hydantoines of general formula (II)_(H), diagram 23, in whichA, X, Y and Het are as defined above, are prepared in 2 stages startingfrom the isocyanates of general formula (XVIII)_(H) describedpreviously. The reaction of the ethyl ester of sarcosine with theisocyanates of general formula (XVIII)_(H), is carried out according toan experimental protocol described in the literature (J. HeterocyclicChem., (1979), 16, 607-608), leads to the formation of the heterocycleof the compounds of general formula (XXI)_(H). The substitution of thehydantoin is carried out in the presence of a weak base, β-alanine, andan aldehyde of general formula (XX)_(H) according to the experimentalconditions described in J. Med. Chem., (1994), 37, 322-328.

[0557] When:

[0558] Het=pyrrolidine, thiazolidine

[0559] X=—NH—CO—X′— and Y=—O—Y′— or —Y′—.

[0560] The carboxamides of general formula (V)_(H), diagram 24, in whichA, X, Y and Het are as defined above, are prepared by condensation ofthe anilines of general formula (XV)_(H), described previously, with theacids of general formula (XXII)_(H) under standard conditions forpeptide synthesis. The syntheses of carboxylic acids (XXII)_(H), whichare nont commercially available, are described below.

[0561] When:

[0562] Het=tetrahydropyridine

[0563] and Y=—CO—NH—Y′—.

[0564] The ureas of general formula (II)_(H), diagram 25, in which A, X,Y and Het are as defined above, are prepared by condensation of theheterocyclic amines of general formula (VIII)_(H), described previously,with the isocyanates of general formula (XVIII)_(H) (cf. above) in asolvent such as dichloromethane, at 20° C., in the presence of atertiary amine (e.g. diisopropylethylamine).

[0565] When:

[0566] Het=pyrrolidine, thiazole, thiadiazole

[0567] and X=—CO—NH—X′—.

[0568] The carboxamides of general formula (II)_(H), diagram 26, inwhich A, X, Y and Het are as defined above, are prepared by condensationof commercial carboxylic acids of general formula (XXIII)_(H) with theamines of general formula (XXIV)_(H) under standard conditions forpeptide synthesis. The syntheses of the amines of general formula(XXIV)_(H), which are not commercially available, are described below.

[0569] When:

[0570] Het=imidazole, oxazole and thiazole

[0571] and Y=—CH(R₃)—N(R₃)—CO—Y′—.

[0572] The carboxamides of general formula (V)_(H), diagram 27, in whichA, X, Y and Het are as defined above, are prepared by condensation ofthe amines of general formula (XXV)_(H) with commercial carboxylic acids(or the corresponding acid chlorides) of general formula (XXVI)_(H)under standard conditions for peptide synthesis. The synthesis of theimidazole derivatives of general formula (XXV)_(H) is described below.

[0573] When:

[0574] Het=imidazole

[0575] and Y=—CH₂—N(R₃)—Y′—.

[0576] The amines of general formula (V)_(H), diagram 28, in which A, X,Y and Het are as defined above, are prepared by condensation of theamines of general formula (XXV)_(H) (see below) with the commercialhalogenated derivatives of general formula (IX)_(H) under the conditionsdescribed previously.

[0577] When:

[0578] Het=dihydroimidazole-2-one

[0579] and Y=—CO—Y′.

[0580] The amines of general formula (II)_(H), diagram 29, in which A,X, Y and Het are as defined above, are prepared by condensation of theamines of general formula (VIII)_(H) (see below) with the commercialhalogenated derivatives of general formula (XXVII)_(H), for example inan acetonitrile and THF mixture and in the presence of a base such asK₂CO₃.

[0581] When:

[0582] Het=oxazolidinone

[0583] and Y=—Y′—O—.

[0584] The oxazolidinones of general formula (II)_(H), diagram 30, areprepared starting from the diols of general formula (XXVII)_(H) thesynthesis of which is described in the literature (Daumas, M.,Tetrahedron, 1992, 48(12), 2373). The formation of carbonates of generalformula (XXVIII)_(H) is obtained, for example, in the presence ofcarbonyl di-imidazole (Kutney, J. P., Synth. Commun., 1975, 5 (1), 47)or in the presence of triphosgene at low temperature as described inSynth. Commun., 1994, 24 (3), 305. The formation of oxazolidinone occursduring heating of the amines of general formula (XV)_(H) with thecarbonates of general formula (XXVIII)_(H) in the presence of an acidcatalyst, such as ZnCl₂, to xylene reflux in order to eliminate thewater formed during the reaction (Laas, H., Synthesis, 1981, 958).

[0585] When:

[0586] Het=isoxazoline, isoxazole, oxazole, thiazole

[0587] and Y=—Y′—CO—NH—Y′—.

[0588] The carboxamides of general formula (II)_(H), diagram 31, inwhich A, X, Y and Het are as defined above, can be prepared startingfrom the commercial amines of general formula (XIV)_(H) and thecarboxylic acids of general formula (XXVIII)_(H) by condensation in thepresence of isobutyl chloroformate (Org. Prep. Proced. Int., (1975), 7,215).

[0589] The preparation of the oxazoles of general formula (XXVIII)_(H)is carried out according to an experimental protocol described inTetrahedron Lett., 1994, 35 (13), 2039. Similarly for the synthesis ofthe thiazoles of general formula (XXVIII)_(H) : J. Med. Chem., 1983, 26,884. The preparation of the isoxazolines is described below.

[0590] When:

[0591] Het=pyrrolidine, piperidine X=—CO—NH— and Y=—O—Y′—.

[0592] The carboxamides of general formula (II)_(H), diagram 32, inwhich A, X, Y and Het are as defined above, can be prepared bycondensation of the commercial carboxylic acids of general formula(XXIII)_(H) with the amines of general formula (XXIX)_(H) under standardconditions for peptide synthesis. The syntheses of amines of generalformula (XXIX)_(H) are described below.

[0593] When:

[0594] Het=isoxazoline, oxazole, thiazole, imidazole

[0595] and Y=—Y′—O—Y′— or —Y′—N(R₃)—Y′—.

[0596] The etheroxides of general formula (II)_(H), Diagram 33, in whichA, X, Y and Het are as defined above, can be prepared starting from theesters of general formula (XXVIII.4)_(H), diagram 31.1, by reaction withhydrides, for example LiAlH₄, in a solvent such as, for example,anhydrous THF. The primary alcohols thus obtained are then condensed onhalogenated derivatives of general formula (IX)_(H) using a base such asfor example KOH in an organic medium and in the presence of a phasetranfer catalyst such as for example Aliquat 336.

[0597] The primary alcohols (XXXI)_(H) can also be activated in the formof sulphonate derivatives, by tosyl chloride in the presence ofpyridine, in order to produce intermediates of general formula(XXXII)_(H). The condensation of alcohols of general formula(XXII.2)_(H) is then carried out in the presence of a strong base, suchas, for example, NaH, in an aporotic solvent (THF or DMF) at atemperature comprised between 20° C. and 80° C., in order to obtain theether oxide of general formula (II)_(H).

[0598] Similarly, the amines of general formula (II)_(H), diagram 33,are obtained by the substitution of the tosylate function of theintermediates of general formula (XXXII)_(H), obtained in a standardfashion starting from the alcohols of general formula (XXXI)_(H) andtosyl chlosride in the presence of pyridine, by the commercial amines ofgeneral formula (XXX)_(H) by reaction in a solvent such as, for example,acetonitrile or DMF, in the presence of a base (K₂CO₃) at a temperaturecomprised between 20 and 85° C.

[0599] When:

[0600] Het=azetidine

[0601] X=—CO—NH— and Y=—O—Y′—.

[0602] The carboxamides of general formula (III)_(H), diagram 34, inwhich A, X, Y and Het are as defined above, can be prepared bycondensation of commercial carboxylic acids of general formula(XXIII)_(H) with the amines of general formula (XXXII)_(H) understandard conditions for peptide synthesis. The synthesis of amines ofgeneral formula (XXXII)_(H) is descried below. The deprotection of theaniline is carried out by a strong acid such as, for example,trifluoroacetic acid optionally in the presence of triethylsilane.

[0603] When:

[0604] Het=azetidine

[0605] X=—NH—CO—X′—

[0606] and Y=—O—Y′—.

[0607] The ureas of general formula (III)_(H), diagram 35, in which A,X, Y and Het are as defined above, can be prepared by the addition ofthe amines of general formula (XXXII)_(H) on the isocyanates (XXXIV)_(H)obtained from the reaction of the amines of general formula (XV)_(H)with triphosgene in the presence of a tertiary amine such as for examplediisopropylethylamine in a neutral solvent such as dichloromethane (J.Org. Chem. (1994), 59 (7), 1937-1938). The ureas of general formula(XXXV)_(H) thus obtained are deprotected by treatment in a strong acidmedium as described previously. The synthesis of the amines of generalformula (XXXII)_(H) is described below.

[0608] When:

[0609] Het thiazole

[0610] and Y=—CH₂—N(R₃)—Y′—.

[0611] The amines of general formula (II)_(H), diagram 36, in which A,X, Y and Het are as defined above, are prepared by condensation of theamines of general formula (XXV)_(H) (see below) with the commercialhalogenated derivatives of general formula (IX)_(H) under the conditionsdescribed previously.

[0612] Preparation of Different Synthesis Intermediates:

[0613] Synthesis of Intermediates (VIII)_(H):

[0614] The syntheses of the intermediates of general formula (VIII)_(H)are illustrated in diagrams 16.1 and 16.2.

[0615] The intermediates of general formula (VIII)_(H), diagram 16.1,can be prepared, for example, in 3 stages starting from 4-imidazolecarboxylic acid. The protection of the nitrogen of the heterocycle iscarried out using (Boc)₂O in the presence of a base such as KiCO₃ inDMF. The condensation with the amines of general formula (XV)_(H) (seeabove) is carried out in a standard fashion under the conditions forpeptide synthesis in order to produce the intermediates of generalformula (VIII.3)_(H). The amine of the heterocycle is regenerated bytreatment in an acid medium and in particular with trifluoroacetic acidin order to produce the intermediates of general formula (VIII)_(H).

[0616] The dihydroimidazole-2-ones of general formula (VIII)_(H),diagram 16.2, can be prepared, for example, in 2 stages starting fromthe anilines of general formula (XV)_(H) (see above) which are condensedon 2-chloroethyl isocyanate in DMF at 20° C. in order to produce theureas of general formula (VIII.4)_(H). The cyclization to produce(VIII)_(H) is then carried out by treatment in a basic medium using, forexample, tBuOK in DMF.

[0617] Synthesis of Intermediates (X)_(H):

[0618] The intermediates of general formula (X)_(H), diagram 17.1, canbe prepared starting from commercial carboxylic acids of general formula(X.1)_(H). Protection of the amine function in the form of a carbamateis followed by the selective reduction of the carboxylic acid functionby lithium and aluminium hydride in a solvent such as THF, at 20° C.Intermediate (X.3)_(H) is then brominated in the presence of carbontetrabromide and triphenylphosphine in a solvent such asdichloromethane.

[0619] Synthesis of Intermediates (XIII)_(H):

[0620] The intermediates of general formula (XIII)_(H), diagram 19.1,can be prepared starting from (R or S) derivatives of thiazolidinecarboxylic acids in the presence of (Boc)₂O under standard conditions.

[0621] Synthesis of Intermediates (XVI)_(H):

[0622] The intermediates of general formula (XVI)_(H), diagram 20.1, canbe prepared starting from commercial carboxamide derivatives of generalformula (XVI.1)_(H). These carboxamides are treated by a Lawessonreagent in a solvent such as 1,4-dioxane for 2 to 3 hours at atemperature which varies from 25° C. to reflux temperature of themixture. The thiocarboxamides of general formula (XVI.2)_(H) are thentreated by ethyl bromopyruvate, at 20° C. in DMF according to anexperimental protocol described in J. Med. Chem., (1983), 26, 884-891,in order to produce the thiazoles of general formula (XVI.3)_(H). Thesaponification of the ester is carried out over 15 hours by aqueouspotash in solution in acetone.

[0623] The tetrahydropyridines of general formula (XVI)_(H), diagram20.2, can be prepared starting from commercial tetrahydro-4-pyridinecarboxylicacid. Esterification is carried out in a standard fashion inthe presence of para-toluene sulphonic acid, in methanol, in order toproduce to the intermediate (XVI.4)_(H) which is then condensed on ahalogenated derivative of general formula (IX)_(H) under the conditionsdescribed previously. The acid of general formula (XVI)_(H) is obtainedby saponification in the presence of, for example, LiOH or KOH.

[0624] Synthesis of Intermediates (XXII)_(H):

[0625] The syntheses of intermediates of general formula (XXII)_(H) aredescribed in diagrams 10.1 and 10.2.

[0626] The tosyylate function of the (L or D) proline derivatives ofgeneral formula (XXII.1)_(H) (Tetrahedron Lett., (1983), 24 (33),3517-3520), diagram 24.1, is substituted by the alcoholate of thederivaties of general formula (XXII.2)_(H), generated in situ by a basesuch as NaH. The substitution is carried out at 20° C. in a solvent suchas N-methylpyrrolidinone which produces the appropriate inversion of theconfiguration of the carbon seat of the reaction (Tetrahedron Lett.,(1983), 24 (33), 3517-3520). The intermediates of general formula(XXII.3)_(H) thus obtained are then saponified in a standard fashion byalcoholic potash.

[0627] The intermediates of general formula (XXII)_(H) can also beprepared (diagram 24.2) starting from the condensation of cysteine (L orD) on an aldehyde of general formula (XXII.5)_(H) according to anexperimental protocol described in the literature (J. Org. Chem.,(1957), 22, 943-946). The amine of the heterocycle is then protected inthe form of a carbamate in order to produce intermediates of generalformula (XXII)_(H). The aldehydes of general formula (XXII.5)_(H), whichare not commercially available, can be prepared according to J. Chem.Soc., Perkin Trans. I, 1973, 1, 35.

[0628] Synthesis of Intermediates (XXIV)_(H):

[0629] The synthesis of intermediates of general formula (XXIV)_(H) isdescribed in diagram 26.1.

[0630] The condensation of the amines (R or S) of general formula(XXIV.1)_(H), diagram 26.1, on the halogenated derivatives of generalformula (IX)_(H) is carried out in the presence of a base such aspotassium carbonate in a solvent such as DMF. The condensation product(XXIV.2)_(H) is then deprotected in an acid medium in order to produceintermediates of general formula (XXIV)_(H).

[0631] Synthesis of Intermediates (XXV)_(H):

[0632] The syntheses of intermediates of general formula (XXV)_(H) aredescribed in diagrams 27.1, 27.2, 27.3 and 27.4.

[0633] The imidazoles of general formula (XXV)_(H), diagram 27.1, can beprepared in 4 stages starting from the commercial compounds (XXV.1)_(H)and (XXV.2)_(H). The condensation between the bromoacetophenones ofgeneral formula (XXV.1)_(H) and the carboxylic acids of general formula(XXV.2)_(H) is carried out in the presence of Caesium carbonate in DMF.The ketoester obtained (XXV.3)_(H) is cyclized in the presence of 15equivalents of ammonium acetate by heating in a mixture of xylenes andsimultaneous elimination of the water formed during the reaction inorder to produce the imidazoles of general formula (XXV.4)_(H). Thenitrogen of the heterocycle is then protected, for example using2-(trimethylsilyl)ethoxymethyl (SEM) or by another protective groupmentioned in: Protective groups in organic synthesis, 2nd ed., (JohnWiley & Sons Inc., 1991), in order to produce intermediates of generalformula (XXV.5)_(H). The release of the amine from the chain can becarried out by hydrogenolysis in the presence of Pd/C.

[0634] Alternatively, the intermediates of general formula (XXV.4)_(H)can be alkylated in the presence of a base such as, for example, K₂CO₃,and a reagent such as R₃—X in a solvent such as DMF or acetonitrile inorder to produce the imidazoles of general formula (XXV.6)_(H).Deprotection of the side chain, as described previously, allows theintermediates of general formula (XXV)_(H) to be accessed.

[0635] The intermediates of general formula (XXV)_(H) containing anoxazole, thiazole or an imidazole are also accessible via othersynthetic routes such as that described in Bioorg. and Med. Chem.Lett.,1993, 3, 915 or Tetrahedron Lett., 1993, 34, 1901. Theintermediates of general formula (XXV.7)_(H) thus obtained can bemodified, diagram 27.2, by saponification followed by decarboxylation,for example thermic, in order to produce disubstituted heterocycles ofgeneral formula (XXV.9)_(H). Release of the amine from the side chain,as described previously, allows the intermediates of general formula(XXV)_(H) to be accessed.

[0636] Alternatively, the carboxylic function of the heterocycles ofgeneral formula (XXV.7)_(H), can be reduced, for example by NaBH₄, inorder to produce alcoholic derivatives of general formula (XXV.10)_(H),diagram 27.3, which can be alkylated in the presence of R₃—X and a basesuch as K₂CO₃ in a solvent such as acetonitrile or DMF. Release of theamine from the side chain, as described previously, allows theintermediates of general formula (XXV)_(H) to be accessed.

[0637] The thiazoles of general formula (XXV)_(H), diagram 27.4, canalso be prepared in 4 stages starting from commercial sarcosinamidehydrochloride. The amine is first protected in a standard fashion in theform of tBu carbamate and the carboxamide function is converted intothiocarboxamide in the presence of Lawesson reagent. The formation ofthe thiazole ring is carried out by the reaction of thiocarboxamide withthe intermediate of general formula (XXV.1)_(H) according to anexperimental protocol described in the literature (J. Org. Chem.,(1995), 60, 5638-5642). The amine function is regenerated by treatmentwith the intermediate of general formula (XXV.12)_(H) in a strong acidmedium such as, for example, trifluoroacetic acid.

[0638] Synthesis of Intermediates (XXVIII)_(H):

[0639] The isoxazolines and isoxazoles of general formula (XXVIII)_(H),Diagram 31.1, are prepared by reaction of commercial aldehydes ofgeneral formula (XX)_(H) with hydroxylamine hydrochloride. The oxime ofgeneral formula (XXVIII.1)_(H) thus obtained is activated in the form ofthe oxime chloride, of general formula (XXVIII.2)_(H), by reaction withN-chlorosuccinimide in DMF before reacting with the esters of generalformula (XXVIII.3)_(H) in order to produce isoxazoline derivatives orwith the esters of general formula (XXVIII.4)_(H) in order to produceisoxazole derivatives according to an experimental protocol described inthe literature (Tetrahedron Lett., 1996, 37 (26), 4455; J. Med. Chem.,1997, 40, 50-60 and 2064-2084). Saponification of the isoxazolines orisoxazoles of general formula (XXVIII.5)_(H) is then carried out in astandard fashion under the conditions described previously.

[0640] The unsaturated esters of general formula (XXVIII.3)_(H) and(XXVIII.4)_(H), which are not commercially available, can be preparedaccording to methods described in the literature (J. Med. Chem., 1987,30, 193; J. Org. Chem., 1980, 45, 5017).

[0641] Synthesis of Intermediates (XXIX)_(H):

[0642] The syntheses of intermediates of general formula (XXIX)_(H) aredescribed in diagrams 32.1, 32.2, 32.3 and 32.4

[0643] The intermediates of general formula (XXIX)_(H) can be prepared,diagram 32.1, starting from the intermediates of general formula(XXII.3)_(H), described previously, by treatment in a strong acid mediumto regenerate the heterocyclic amine function. The selective reductionof the carboxylic function in the presence of, for example, sodiumborohydride in a solvent such as, for example, anhydrous THF, allows theintermediate of general formula (XXIX)_(H) carrying a primary alcoholfunction to be obtained without touching the nitro group (Rao, A. V. R.,J. Chem. Soc. Chem. Commun., 1992, 11, 859).

[0644] The intermediates of general formula (XXIX)_(H) can also beprepared, diagram 32.2, starting from intermediates of general formula(XXIX.1)_(H) (R or S) the preparation of which is similar to that of thecompounds of general formula (XXII.1)_(H). Condensation of the alcoholicderivatives of general formula (XXII.2)_(H) on the intermediates ofgeneral formula (XXIX.1)_(H) is also described above. Release of theheterocyclic amine is carried out in the presence of an organic solutionof a strong acid, for example, trifluoroacetic acid.

[0645] The amines of general formula (XXIX)_(H), diagram 32.3, are alsoaccessible starting from the substitution of tosylated derivatives ofgeneral formula (XXIX.1)_(H) by the commercial amines of general formula(XXX)_(H). Detachment of the carbamate function from the intermediatesof general formula (XXIX.3)_(H) is carried out as described previously.

[0646] The intermediates of general formula (XXIX)_(H) can also beprepared, diagram 32.4, by reaction of the halogenated derivatives ofgeneral formula (IX)_(H) with an alcohol of general formula (XXIX.4)_(H)in the presence of a base such as for example tBuO⁻K⁺ in an anhydroussolvent such as THF. The intermediate of general formula (XXIX.5)_(H)thus obtained is then deprotected in a strong acid medium (HCl or TFA).

[0647] Synthesis of Intermediates (XXXII)_(H):

[0648] The intermediates of general formula (XXXII)_(H) can be prepared,diagram 34.1, by reaction of the halogenated derivatives of generalformula (IX)_(H) with commercial 1-(diphenylmethyl)-3-hydroxyazetidine(XXXII.1)_(H) in the presence of a base such as for example NaH in ananhydrous solvent such as THF. In this case, the nitro group of theintermediate of general formula (XXXII.2)_(H) is reduced in the presenceof SnCl₂, as described previously, in order to produce the intermediateof general formula (XXXII.3)_(H) the amine of which is then protected inthe form of a tButyl carbamate. The detachment of the diphenylmethylprotective group is then carried out in a standard fashion byhydrogenolysis in the presence of Pd(OH)₂ in order to produce theintermediate of general formula (XXXII)_(H).

[0649] Unless they are defined differently, all the technical andscientific terms used here have the same meaning as that usuallyunderstood by an ordinary specialist in the field to which the inventionbelongs. Similarly, all publications, Patent Applications, Patents andother references mentioned here are incorporated by way of reference.

[0650] The following examples are presented to illustrate the aboveprocedures and should in no way be considered as restricting the scopeof the invention.

EXAMPLES Example 13,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-benzamide Hydrochloride: 1

[0651] 1.1)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-nitrophenyl)-benzamide:

[0652] 1.38 g (10 mmoles) of 4-nitroaniline, 2.5 g (10 mmoles) of3,5-di-tert-butyl-4-hydroxybenzoic acid and 2.26 g (11 mmoles) ofdicyclohexylcarbodiimide are introduced into a 250 ml flask containing20 ml of THF. The reaction medium is agitated for 15 hours at ambienttemperature, and the precipitate which appears is filtered out andrinsed with ethyl acetate After the solution is concentrated underreduced pressure, the residue is diluted in 20 ml of ethyl acetate andthe insoluble part is filtered out. The solvent is eliminated undervacuum and the residue is precipitated from diethyl ether. The solid isrecovered by filtration, rinsed abundantly with diethyl ether in orderto produce a white powder with a yield of 65%. Melting point: 277-278°C.

[0653] NMR ¹H (100 MHz, DMSO d6, δ): 10.72 (s, 1H, CONH); 8.30 (m, 4H,Ph—NO₂); 7.80 (s, 2H, Ph); 1.60 (s, 18H, 2×tBu).

[0654] 1.2)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide:

[0655] In a 250 ml Parr flask, 2.4 g (6.5 mmoles) of3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-nitrophenyl)-benzamide isdissolved in 50 ml of an absolute ethanol/dichloromethane mixture (1/1)in the presence of 10% Pd/C. The mixture is agitated under 20 PSI ofhydrogen, at 30° C., for one hour. After filtration on celite, thefiltrate is concentrated under vacuum. The evaporation residue is takenup in 25 ml of a 1M HCl solution. The precipitate formed is filtered andrinsed with 50 ml of diethyl ether followed by 50 ml of ethyl acetate.The amine is released from its salt by agitation in a mixture of 50 mlof ethyl acetate and 50 ml of 1M NaOH. After decanting, the organicphase is washed with 25 ml of 1M NaOH and 25 ml of brine. The organicsolution is dried over sodium sulphate, filtered, rinsed andconcentrated to dryness under reduced pressure to produce 1.09 g (49%)of a white powder. Melting point: 220-221° C.

[0656] NMR ¹H (100 MHz, DMSO d6, δ): 9.80 (s, 1H, CONH); 7.78 (s, 2H,Ph); 7.05 (m, 4H, Ph—NH₂); 5.02 (s, 2H, OH); 1.60 (s, 18H, 2×tBu).

[0657] 1.3) 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-benzamide Hydrochloride: 1

[0658] 880 mg (3.08 mmoles) of S-methyl-2-thiophenethiocarboximidehydriodide (Ann. Chim. (1962), 7, 303-337) is introduced into a 100 mlflask containing a solution of 1.05 g (3.08 mmoles) of3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)benzamide in 20ml of 2-propanol. After heating at 50° C. for 15 hours, the reactionmedium is concentrated to dryness under vacuum. The residue is taken upin 50 ml of ethyl acetate and 50 ml of a saturated solution of sodiumcarbonate. After decanting, the organic phase is washed successivelywith 50 ml of a saturated solution of sodium carbonate, 50 ml of waterand 50 ml of brine. The organic solution is dried over sodium sulphate,filtered and evaporated under reduced pressure. The crystals obtainedare taken up in diethyl ether, filtered and washed successively withethyl acetate and acetone. 0.77 g of base is obtained with a yield of58%.

[0659] The hydrochloride is prepared from 0.77 g (1.71 mmole) of basedissolved in 60 ml of methanol and salified in the presence of 3.42 ml(3.42 mmoles) of a molar solution of HCl in anhydrous diethyl ether.After agitating for 30 minutes at ambient temperature, the solvent isevaporated off under vacuum and the residue precipitated in the presenceof diethyl ether. The crystals obtained are filtered and rinsedabundantly with diethyl ether in order to finally produce after drying0.65 g (43%) of a pale yellow powder. Melting point: 290-291° C.

[0660] NMR ¹H (400 MHz, DMSO d6, δ): 11.55 (s, 1H, NH⁺); 10.40 (s, 1H,CONH); 9.83 (s, 1H, NH⁺); 8.85 (s, 1H, NH⁺); 8.21 (m, 2H, thiophene);7.70 (s, 2H, Ph); 7.67 (m, 4H, Ph—NH); 7.60 (s, 1H, OH); 7.40 (m, 1H,thiophene); 1.42 (s, 18H, 2×tBu).

[0661] IR: ν_(OH): 3624 cm⁻¹, 3430 cm⁻¹; ν_(C═O) (amide): 1653 cm⁻¹;ν_(C═N) (amidine): 1587 cm⁻¹.

Example 23,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamideHydrochloride: 2

[0662] 2.1)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide:

[0663] 1.88 g (10 mmoles) of p-nitrobenzylamine hydrochloride, 2.5 g (10mmoles) of 3,5-di-tert-butyl-4-hydroxybenzoic acid, 1.38 ml (10 mmoles)of triethylamine and 2.26 g (11 mmoles) of dicyclohexylcarbodiimide areintroduced into a 250 ml flask containing 25 ml of THF. The reactionmedium is agitated for 15 hours at ambient temperature, the precipitatewhich appears is filtered out and rinsed with the minimum quantity ofethyl acetate. After concentration of the solution under reducedpressure, the residue is precipitated from a mixture of ethylacetate/diethyl ether (1/4) and filtered. The crystals are washedabundantly with diethyl ether in order to finally produce, after drying,a white powder with a yield of 74% (2.85 g). Melting point: 230-231° C.

[0664] NMR ¹H (100 MHz, CDCl₃, δ): 7.85 (m, 4H, Ph—NO₂); 7.69 (s, 2H,Ph); 6.82 (m, 1H, NHCO); 5.67 (s, 1H, OH); 4.75 (d, 2H, CH ₂—NHCO, J=6.5Hz); 1.49 (s, 18H, 2×tBu).

[0665] 2.2)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-aminophenyl)methyl]-benzamide:

[0666] In a 250 ml Parr flask, 2.85 g (7.4 mmoles) of3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamideis dissolved in 30 ml of an absolute ethanol/dichloromethane mixture(1/1) in the presence of 10% Pd/C. The mixture is agitated under 20 PSIof hydrogen, at 30° C., for one hour. After filtration on celite, thefiltrate is concentrated under vacuum. The evaporation residuecrystallizes spontaneously. It is left to rest overnight, the crystalsare filtered out and rinsed with a mixture of diethyl ether (45 ml) andacetone (5 ml). 1.63 g (62%) of a white powder is obtained. Meltingpoint: 188-189° C.

[0667] NMR ¹H (100 MHz, CDCl₃, δ): 7.62 (s, 2H, Ph); 6.95 (m, 4H,Ph—NH₂); 6.20 (m, 1H, NHCO); 5.58 (s, 1H, OH); 4.50 (d, 2H, CH ₂—NHCO,J=6.5 Hz); 3.70 (wide s, 2H, NH₂); 1.47 (s, 18H, 2×tBu).

[0668] 2.3)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[[(2-thienyl-(imino)methyl)amino]phenyl]methyl}-benzamideHydrochloride: 2

[0669] The experimental protocol used is the same as that described forcompound 1, with3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-aminophenyl)methyl]-benzamidereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Aftersalification with a molar solution of HCl in anhydrous diethyl ether, awhite powder is obtained with a yield of 56%. Melting point: 218-219° C.

[0670] NMR ¹H (400 MHz, DMSO d6, δ): 11.60 (s, 1H, NH⁺); 9.83 (s, 1H,NH⁺); 9.02 (s, 1H, CONH); 8.90 (s, 1H, NH⁺); 8.18 (m, 2H, thiophene);7.70 (s, 2H, Ph); 7.42 (m, 6H, thiophene, Ph—NH, OH); 4.50 (d, 2H, CH₂—NHCO, J=5.7 Hz); 1.40 (s, 18H, 2×tBu).

[0671] IR: ν_(OH): 3624 cm⁻¹, 3424 cm⁻¹; ν_(C═O) (amide): 1644 cm⁻¹;ν_(C═N) (amidine): 1568 cm⁻¹.

Example 34-acetoxy-3,5-dimethoxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide:3

[0672] 3.1) 4-acetoxy-3,5-dimethoxy-benzoic Acid:

[0673] In a 100 ml flask, under a nitrogen atmosphere, 1.50 g (7.57mmoles) of syringic acid is dissolved in 15 ml of dry pyridine. 0.86 ml(9.08 mmoles) of acetic anhydride is added dropwise and the mixture isagitated at ambient temperature for 18 hours. The pyridine is evaporatedoff under reduced pressure, the residue is taken up in 25 ml ofdichloromethane and washed with 10 ml of a molar solution of HCl thenwith 2×10 ml of water. The organic phase is dried over sodium sulphate,filtered and evaporated under vacuum. 1.72 g (95%) of a beige powder isobtained. Melting point: 181-183° C.

[0674] NMR ¹H (100 MHz, CDCl₃, δ): 8.15 (s, 1H, CO₂H); 7.40 (s, 2H, Ph);3.90 (s, 6H, 2×OCH₃); 2.40 (s, 3H, CH₃).

[0675] 3.2) 4-acetoxy-3,5-dimethoxy-N-[(4-nitrophenyl)methyl]-benzamide:

[0676] The experimental protocol used is the same as that described forintermediate 2.1, 4-acetoxy-3,5-dimethoxy-benzoic acid replacing the3,5-di-tert-butyl-4-hydroxy-benzoic acid. A colourless oil is obtainedwith a yield of 28%.

[0677] NMR ¹H (100 MHz, DMSO d6, δ): 9.26 (t, TH, NHCO, J=6.0 Hz); 7.91(m, 4H, Ph—NO₂); 7.31 (s, 2H, Ph); 4.65 (d, 2H, CH₂, J=6.0 Hz); 3.83 (s,6H, 2×OCH₃); 2.28 (s, 3H, CH₃).

[0678] 3.3) 4-acetoxy-3,5-dimethoxy-N-[(4-aminophenyl)methyl]-benzamide:

[0679] The experimental protocol used is the same as that described forintermediate 2.2,4-acetoxy-3,5-dimethoxy-N-[(4-nitrophenyl)methyl]-benzamide replacingthe3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.A colourless oil is obtained with a yield of 82%. The product is useddirectly in the following stage without additional purification.

[0680] 3.4) 4-acetoxy-3,5-dimethoxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide: 3

[0681] The experimental protocol used is the same as that described forcompound 1, with4-acetoxy-3,5-dimethoxy-N-[(4-aminophenyl)methyl]-benzamide replacingthe 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide.The base 3 in the form of a beige powder is obtained with a yield of65%. Melting point: 47-48° C.

[0682] NMR ¹H (400 MHz, DMSO d6, δ): 9.08 (wide s, 1H, CONH); 7.75 (m,1H, thiophene); 7.62 (m, 1H, thiophene); 7.30 (s, 2H, Ph); 7.10 (m, 1H,thiophene); 7.07 (m, 4H, Ph—N); 6.48 (wide s, 2H, NH₂); 4.50 (d, 2H,CH₂, J=4.6 Hz); 3.80 (s, 6H, 2×OCH₃); 2.30 (s, 3H, CH₃).

[0683] IR: ν_(C═O) (ester): 1760 cm^(−1;) ν_(C═O) (amide): 1630 cm^(−1;)ν_(C═N) (amidine): 1540 cm⁻¹.

Example 43,5-dimethoxy-4-hydroxy-N-{4-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamide:4

[0684] In a 50 ml flask, 1 ml (2 mmoles) of 2N hydrochloric acid isintroduced dropwise into a solution of 0.59 g (1 mmole) of compound 3 in5 ml of ethanol. The reaction medium is agitated for 18 hours at 50° C.The solvents are evaporated to dryness, the residue is taken up indichloromethane (5 ml) and washed with molar soda solution (3×5 ml).After drying the organic phase, filtration and concentration to drynessis carried out and the oil obtained is purified by chromatography on asilica gel column (eluant: dichloromethane/methanol: 9/1). The purefractions are collected and after evaporation under vacuum a beigepowder is obtained with a yield of 60%. Melting point: 55-58° C.

[0685] NMR ¹H (400 MHz, DMSO d6, δ): 8.92 (s, 1H, OH); 8.84 (m, 1H,CONH); 7.75 (m, 1H, thiophene); 7.63 (m, 1H, thiophene); 7.26 (s, 2H,Ph); 7.10 (m, 1H, thiophene); 7.05 (m, 4H, Ph—N); 6.50 (s, 2H, NH₂);4.45 (d, 2H, CH₂, J=5.7 Hz); 3.81 (s, 6H, 2×OCH₃).

[0686] IR: ν_(OH): 3300 cm^(−1;) ν_(C═O) (amide): 1630 cm^(−1;) ν_(C═N)(amidine): 1590 cm⁻¹.

Example 53,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamideHydriodide: 5

[0687] 5.1)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide:

[0688] 2.02 g (10 mmoles) of 4-nitrophenetylamine hydrochloride, 2.5 g(10 mmoles) of 3,5-di-tert-butyl-4-hydroxy-benzoic acid, 1.38 ml (10mmoles) of triethylamine and 2.26 g (11 mmoles) ofdicyclohexylcarbodiimide are introduced into a 100 ml flask containing20 ml of THF. The reaction medium is agitated for 15 hours at ambienttemperature, the precipitate which appears is filtered out and rinsedwith ethyl acetate. After concentration of the filtrate under reducedpressure, the residue is precipitated from diethyl ether. The solid isrecovered by filtration and rinsed with diethyl ether. A white powder isobtained with a yield of 73%. Melting point: 204-206° C.

[0689] NMR ¹H (100 MHz, CDCl₃, δ): 7.52 (s, 2H, Ph); 6.85 (m, 4H,Ph—NO₂); 6.02 (m, 1H, NHCO); 3.62 (m, 2H, CH ₂—NHCO); 2.82 (m, 2H, CH₂—Ph—NO₂); 1.48 (s, 18H, 2×tBu).

[0690] 5.2)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-aminophenyl)ethyl]-benzamide:

[0691] The experimental protocol used is the same as that described forintermediate2.2,3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamidereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.A white powder is obtained with a yield of 76%. Melting point: 193-195°C.

[0692] NMR ¹H (100 MHz, CDCl₃, δ): 7.80 (m, 4H, Ph—NH₂); 7.55 (s, 2H,Ph); 6.10 (m, 1H, NHCO); 5.55 (s, 1H, OH); 3.75 (m, 2H, CH ₂—NHCO); 3.10(m, 2H, CH ₂—Ph—NH₂); 1.50 (s, 18H, 2×tBu).

[0693] 5.3)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{4-[2-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamideHydriodide: 5

[0694] 0.78 g (2.74 mmoles) of S-methyl-2-thiophene-thiocarboximidehydriodide (Ann. Chim. (1962), 7, 303-337) is introduced into a 50 mlflask containing 1.01 g (2.74 mmoles) of3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-aminophenyl)ethyl]-benzamidedissolved in 20 ml of 2-propanol. The reaction medium is heated at 40°C. for 4 hours. The solvent is evaporated off under vacuum and theresidue is precipitated in the presence of 50 ml of a water/ethylacetate mixture (1/1). The crystals formed are filtered out and washedsuccessively with ethyl acetate and diethyl ether. After drying, a paleyellow powder is obtained with a yield of 68%. Melting point: 185-186°C.

[0695] NMR ¹H (400 MHz, DMSO d6, δ): 9.80 (s, 1H, NH⁺); 8.88 (s, 1H,NH⁺); 8.40 (s, 1H, CONH); 8.12 (m, 2H, thiophene); 7.60 (s, 2H, Ph);7.42 (m, 6H, thiophene, Ph—NH, OH); 3.52 (d, 2H, CH ₂—NHCO, J=5.9 Hz);2.90 (m, 2H, CH ₂—Ph—NH); 1.40 (s, 18H, 2×tBu).

[0696] IR: ν_(OH): 3624 cm⁻¹, 3423 cm⁻¹; ν_(C═O) (amide): 1636 cm⁻¹;ν_(C═N) (amidine): 1569 cm⁻¹.

Example 64-acetoxy-3,5-dimethoxy-N-{4-[2-[(2-thienyl-(imino)methyl)amino]phenyl]ethyl}-benzamideFumarate: 6

[0697] 6.1)4-acetoxy-3,5-dimethoxy-N-[2-(4-nitrophenyl)ethyl]-benzamide:

[0698] The experimental protocol used is the same as that described forintermediate 5.1, with 4-acetoxy-3,5-dimethoxy-benzoic acid(intermediate 3.1) replacing the 3,5-di-tert-butyl-4-hydroxy benzoicacid. A colourless oil is obtained with a yield of 70%. The product isused directly in the following stage.

[0699] 6.2)4-acetoxy-3,5-dimethoxy-N-[2-(4-aminophenyl)ethyl]-benzamide:

[0700] The experimental protocol used is the same as that described forintermediate 2.2, with4-acetoxy-3,5-dimethoxy-N-[2-(4-nitrophenyl)ethyl]-benzamide replacingthe3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.A colourless oil is obtained with a quantitative yield. The product isused directly in the following stage without additional purification.

[0701] 6.3)4-acetoxy-3,5-dimethoxy-N-{4-[2-[(2-thienyl(imino)methyl)amino]-phenyl]ethyl}-benzamideFumarate: 6

[0702] The experimental protocol used to produce the free base is thesame as that described for the synthesis of compound 1, with4-acetoxy-3,5-dimethoxy-N-[2-(4-aminophenyl)ethyl]-benzamide replacingthe 3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide.

[0703] The product of the reaction is salified in the presence of anequimolar quantity of fumaric acid in ethanol under reflux. Compound 6is obtained in the form of a beige powder with a yield of 74%. Meltingpoint: 178-180° C.

[0704] NMR ¹H (400 MHz, DMSO d6, δ): 8.60 (m, 1H, CONH); 7.75 (m, 1H,thiophene); 7.64 (d, 1H, thiophene, J=5.0 Hz); 7.20 (s, 2H, Ph); 7.11(t, 1H, thiophene, J=9.0 Hz); 7.02 (m, 4H, Ph—N); 6.61 (s, 2H, CH═CHfumarate); 3.81 (s, 6H, 2×OCH₃); 3.50 (q, 2H, CH₂—N, J=6.5 Hz); 2.82 (t,CH ₁₂—Ph, J=7.0 Hz); 2.27 (s, 3H, CH₃).

[0705] IR: ν_(C═O) (ester): 1750 cm⁻¹; ν_(C═O) (amide): 1640 cm⁻¹;ν_(C═N) (amidine): 1550 cm⁻¹.

Example 73,5-dimethoxy-4-hydroxy-N-{4-[2-[(2-thienyl-(imino)methyl)amino]phenyl]ethyl}-benzamideHydrochloride: 7

[0706] In a 50 ml flask, 1.40 ml (2.80 mmoles) of a solution of 2Nhydrochloric acid is added dropwise to a solution of 0.64 g (1.37mmoles) of compound 6 in the form of the free base in 5 ml of ethanol.The reaction medium is agitated for 18 hours at 50° C. The solvents areevaporated to dryness and the evaporation residue is precipitated from amixture of 5 ml of a 2N solution of soda and 10 ml of dichloromethane.After filtration, the solid is taken up in (4N) hydrochloric ethanol. Alight precipitate is then eliminated. The solvent is evaporated underreduced pressure and the residue taken up in acetone. Product 7precipitated in the form of the hydrochloride is obtained with a yieldof 58%. Melting point: 164-167° C.

[0707] NMR ¹H (400 MHz, DMSO d6, δ): 9.80 (wide s, 1H, NH⁺); 8.90 (s,2H, NH⁺, OH); 8.54 (m, 1H, CONH); 8.18 (s, 1H, thiophene); 8.16 (s, 1H,thiophene); 7.40 (m, 4H, Ph—N); 7.21 (s, 2H, Ph); 7.11 (m, 1H,thiophene); 3.81 (s, 6H, 2×OCH₃); 3.51 (q, 2H, CH₂—N, J=7.0 Hz); 2.92(t, CH ₂—Ph, J=7.0 Hz).

[0708] IR: ν_(OH): 3300 cm⁻¹; ν_(C═O) (amide): 1620 cm⁻¹; ν_(C═N)(amidine): 1560 cm⁻¹.

Example 83,4,5-trihydroxy-N-{4-[2-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamidehemi-fumarate: 8

[0709] 8.1) 3,4,5-trihydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide:

[0710] 2 g (11.5 mmoles) of gallic acid, 2.5 g (11.5 mmoles) of4-nitrophenetylamine hydrochloride, 1.8 g (11.5 mmoles) of hydrated1-hydroxybenzotriazole, 2.25 g (11.5 mmoles) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 3.3 ml(23 mmoles) of triethylamine are introduced into a 100 ml flaskcontaining 30 ml of anhydrous DMF. The orange-coloured solution obtainedis agitated at 20° C. for 20 hours and diluted in a mixture ofdichloromethane (50 ml) and water (30 ml). After decanting, the organicphase is washed with a molar solution of hydrochloric acid (20 ml) andwith water (3×20 ml) until neutrality is achieved. After drying theorganic phase over magnesium sulphate, followed by filtration andconcentration under vacuum, the residue is purified on a silica gelcolumn (eluant: dichloromethane/methanol: 9/1). The expected product isobtained in the form of a colourless oil with a yield of 42% (1.57 g).

[0711] NMR ¹H (100 MHz, DMSO d6, δ): 8.95 (m, 3H, 3×OH); 7.85 (m, 4H,Ph—NO₂); 6.80 (s, 2H, Ph); 3.36 (m, 2H, CH₂—N); 2.97 (t, 2H, CH ₂—Ph,J=6.0 Hz).

[0712] 8.2) 3,4,5-trihydroxy-N-[2-(4-aminophenyl)ethyl]-benzamide:

[0713] The experimental protocol used is the same as that described forintermediate 2.2, with3,4,5-trihydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.A beige powder is obtained with a yield of 89%. Melting point: 167-169°C.

[0714] NMR ¹H (100 MHz, DMSO d6, δ): 8.80 (m, 3H, OH); 8.07 (t, 1H,NHCO, J=5.0 Hz); 6.81 (s, 2H, Ph); 6.68 (m, 4H, Ph—NH₂); 3.28 (m, 2H, CH₂—N); 2.60 (t, 2H, CH₂—Ph, J=7.0 Hz).

[0715] 8.3)3,4,5-trihydroxy-N-{4-[2-[(2-thienyl(imino)methyl)amino]-phenyl]ethyl}-benzamidehemi-fumarate: 8

[0716] The experimental protocol used is the same as that described forcompound 1, with 3,4,5-trihydroxy-N-[2-(4-aminophenyl)ethyl]-benzamidereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Base8 is obtained in the form of a powder which is salified, by heatingunder reflux with ethanol, in the presence of one equivalent of fumaricacid. The salt crystallizes spontaneously at 20° C. After filtration andwashing with ethanol the expected product is obtained in the form of abeige powder with a yield of 53%. Melting point: 245-246° C.

[0717] NMR ¹H (400 MHz, DMSO d6, δ): 8.85 (m, 3H, 3×OH); 8.14 (t, 1H,NHCO, J=5.0 Hz); 7.73 (s, 1H, thiophene); 7.60 (d, 1H, thiophene, J=5.0Hz); 7.16 (s, 2H, Ph); 7.09 (t, 1H, thiophene, J=4.0 Hz); 6.80 (m, 4H,Ph—N); 6.59 (wide s, 2H, ½-CH═CH, NH); 3.41 (m, 3H, CH₂—N⁺NH); 2.76 (t,2H, CH₂, J=7.5 Hz).

[0718] IR: ν_(OH): 3300 cm⁻¹; ν_(C═O) (amide): 1620 cm⁻¹; ν_(C═N)(amidine): 1590 cm⁻¹.

Example 9N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamideHydrochloride: 9

[0719] 9.1)2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl}-phenol:

[0720] 2.07 g (10 mmoles) of 1-(4-nitrophenyl)piperazine, 2.5 g (10mmoles) of 3,5-di-tert-butyl-4-hydroxybenzoic acid and 2.26 g (11mmoles) of dicyclohexylcarbodiimide are introduced into a 100 ml flaskcontaining 25 ml of DMF. The reaction medium is agitated for 15 hours atambient temperature, the precipitate which appears is filtered out andrinsed with ethyl acetate. After concentration of the filtrate underreduced pressure, the residue is diluted in 20 ml of ethyl acetate and anew insoluble is eliminated by filtration. The solvent is evaporated offunder vacuum and the residue is precipitated from diethyl ether. Thesolid is filtered, rinsed with 2×20 ml of ethyl acetate in order toobtain a yellow powder with a yield of 89%. Melting point: 159.5-160.5°C.

[0721] NMR ¹H (100 MHz, CDCl₃, δ): 7.58 (m, 4H, Ph—NO₂); 7.30 (s, 2H,Ph); 5.50 (s, 1H, OH); 3.85 (m, 4H, piperazine); 3.55 (m, 4H,piperazine); 1.46 (s, 18H, 2×tBu).

[0722] 9.2)2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-aminophenyl)-1-piperazinyl]-carbonyl}-phenol:

[0723] In a 250 ml Parr flask, 2.19 g (5.0 mmoles) of intermediate 9.1is dissolved in 50 ml of absolute ethanol in the presence of 10% Pd/C.The mixture is agitated under 20 PSI of hydrogen, at 30° C., for onehour. After filtration on celite, the filtrate is concentrated undervacuum. The evaporation residue is taken up in 25 ml of diethyl ether,filtered and rinsed with 2×20 ml of diethyl ether. A pale pink powder isobtained with a yield of 82%. Melting point: 221-222° C.

[0724] NMR ¹H (100 MHz, CDCl₃, δ): 7.30 (s, 2H, Ph); 6.75 (m, 4H,Ph—NH₂); 5.45 (s, 1H, OH); 3.80 (m, 4H, piperazine); 3.10 (m, 4H,piperazine); 1.49 (s, 18H, 2×tBu).

[0725] 9.3)N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamideHydrochloride: 9

[0726] The experimental protocol used is the same as that described forcompound 1, with2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-aminophenyl)-1-piperazinyl]-carbonyl}-phenolreplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Aftertreatment with a molar solution of HCl in anhydrous diethyl ether, abeige powder is obtained with a yield of 75%. Melting point: 235-236° C.

[0727] NMR ¹H (400 MHz, DMSO d6, δ): 11.45 (s, 1H, NH⁺); 9.78 (s, 1H,NH⁺); 8.75 (s, 1H, NH⁺); 8.19 (m, 2H, thiophene); 7.29 (m, 5H, Ph—N,thiophene); 7.10 (s, 2H, Ph); 5.60 (wide s, 1H, OH); 3.70 (m, 4H,piperazine); 3.30 (m, 4H, piperazine); 1.40 (s, 18H, 2×tBu).

[0728] IR: ν_(OH): 3633 cm⁻¹, 3433 cm⁻¹; ν_(C═O) (amide): 1617 cm⁻¹;ν_(C═N) (amidine): 1590 cm⁻¹.

Example 10N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamideHydrochloride: 10

[0729] 10.1) 2,6-bis-(1,1-dimethylethyl)-4-bromomethylphenol:

[0730] In a 250 ml three-necked flask under a nitrogen atmosphere, 2.36g (10 mmoles) of 3,5 di-tert-butyl-4-hydroxybenzylic alcohol isdissolved in 25 ml of anhydrous THF. The solution is cooled down usingan ice bath before the dropwise addition of 0.95 ml (10 mmoles) ofphosphorus tribromide diluted with 25 ml of anhydrous THF. After 15minutes of agitation at 0° C., the solution is diluted with 100 ml ofdichloromethane and washed with 3×30 ml of water followed by 30 ml ofbrine. The organic phase is dried over sodium sulphate, filtered andconcentrated under vacuum to produce a brown oil which is used directlyin the following stage.

[0731] 10.2)2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-methyl}-phenol:

[0732] In a 100 ml flask containing a solution of 2.99 g (10 mmoles) of2,6-bis-(1,1-dimethylethyl)-4-bromomethylphenol in 30 ml of DMF, 1.38 g(10 mmoles) of potassium carbonate and 2.07 g (10 mmoles) of1-(4-nitrophenyl)piperazine are added successively. After agitation fortwo hours at ambient temperature, the reaction medium is diluted with150 ml of dichloromethane and washed successively with 3×40 ml of waterfollowed by 40 ml of brine. The organic solution is dried over sodiumsulphate, filtered and concentrated under reduced pressure. The brownresidue obtained is purified on a silica gel column (eluant: petroleumether (B.p. 40-70° C.)/ethyl acetate: 8/2). After concentration of thepure fractions, 2.31 g (54%) of a brown powder is obtained. Meltingpoint: 177.5-178.5° C.

[0733] NMR ¹H (100 MHz, CDCl₃, δ): 7.50 (m, 4H, Ph—NO₂); 7.12 (s, 2H,Ph); 5.19 (s, 1H, OH); 3.50 (s, 2H, CH ₂—Ph); 3.49 (m, 4H, piperazine);2.60 (m, 4H, piperazine); 1.49 (s, 18H, 2×tBu).

[0734] 10.3)2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-aminophenyl)-1-piperazinyl]-methyl}-phenol:

[0735] The experimental protocol used is the same as that described forintermediate 9.2, with2,6-bis-(1,1-dimethylethyl)-4-{[[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl]-methyl}-phenolreplacing the2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl}-phenol.A pale pink powder is obtained with a yield of 75%. Melting point:152-154° C.

[0736] NMR ¹H (100 MHz, CDCl₃, δ): 7.12 (s, 2H, Ph); 6.78 (m, 4H,Ph—NH₂); 3.59 (s, 2H, CH₂—Ph); 3.18 (m, 4H, piperazine); 2.70 (m, 4H,piperazine); 1.47 (s, 18H, 2×tBu).

[0737] 10.4)N-{4-[4-[3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamideHydrochloride: 10

[0738] 0.43 g (1.5 mmole) of S-methyl-2-thiophene-thiocarboximidehydriodide (Ann. Chim. (1962), 7, 303-337) is introduced into a 100 mlflask containing 0.59 g (1.5 mmole) of intermediate 10.3 in 20 ml of2-propanol. After heating under reflux for 15 hours, the reaction mediumis concentrated to dryness under vacuum. The residue is purified on asilica gel column (eluant: dichloromethane/ethanol: 90/10). The purefractions are concentrated under vacuum and the evaporation residue issalified in the presence of a molar solution of HCl in anhydrous diethylether. A pale yellow powder is obtained with a yield of 40%. Meltingpoint: 234-236° C.

[0739] NMR ¹H (400 MHz, DMSO d6, δ): 11.60 (s, 1H, NH⁺); 11.40 (s, 1H,NH⁺); 9.75 (s, 1H, NH⁺); 8.70 (s, 1H, NH⁺); 8.17 (m, 2H, thiophene);7.39 (s, 2H, Ph); 7.38 (m, 1H, thiophene); 7.24 (m, 5H, Ph—N, OH); 4.26(d, 2H, CH₂—Ph, J=4.6 Hz); 3.90 (m, 2H, piperazine); 3.35 (m, 4H,piperazine); 3.15 (m, 2H, piperazine); 1.41 (s, 18H, 2×tBu).

[0740] IR: ν_(OH): 3624 cm⁻¹, 3418 cm⁻¹; ν_(C═N) (amidine): 1610 cm⁻¹.

Example 11N-{4-[4-[3,5-dimethoxy-4-hydroxybenzoyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamideHydrochloride: 11

[0741] 11.1)2,6-dimethoxy-4-{[4-(4-nitrophenyl)-1-piperazinyl]carbonyl}-phenol:

[0742] In a 100 ml flask, 0.99 g (5 mmoles) of syringic acid, 0.74 g(5.5 mmoles) of hydroxybenzotriazol, 1.10 g (5.5 mmoles) ofdicyclohexylcarbodiimide and 1.04 g (5 mmoles) of1-(4-nitrophenyl)piperazine are dissolved in 10 ml of DMF. Afteragitation at ambient temperature for 7 hours, the mixture is filteredand the precipitate rinsed with 20 ml of DMF followed by 100 ml ofchloroform. 2 g of a yellow powder is obtained, containing approximately20% of dicyclohexylurea. The product is used as it is in the followingstage.

[0743] NMR ¹H (100 MHz, DMSO d6, δ): 7.69 (m, 4H, Ph—NO₂); 6.88 (s, 2H,Ph); 5.72 (m, 1H, OH); 3.91 (s, 6H, 2×OCH₃); 3.75 (m, 4H, piperazine);3.49 (m, 4H, piperazine).

[0744] 11.2)2,6-dimethoxy-4-{[4-(4-aminophenyl)-1-piperazinyl]carbonyl}-phenol:

[0745] In a 250 ml Parr flask, 2 g of intermediate 11.1 is dissolved in40 ml of absolute ethanol/DMSO (1/3) in the presence of 10% Pd/C. Themixture is agitated under 20 PSI of hydrogen, at 25° C., for 15 hours.After filtration on celite, the filtrate is concentrated under vacuum.The brown evaporation residue is taken up in 50 ml of ethyl acetate, theprecipitate formed is eliminated by filtration, rinsed with 20 ml ofethyl acetate and the filtrate extracted with 2×25 ml of a molarsolution of HCl. The aqueous phase is alkalinized by the addition ofpowdered sodium carbonate and extracted with 2×50 ml of ethyl acetate.The organic solution is dried over sodium sulphate, filtered andconcentrated under vacuum. The powder obtained is taken up in 20 ml ofdiethyl ether containing 3 ml of methanol, filtered and rinsed usingdiethyl ether. 400 mg (22% over the two stages) of brown crystals areobtained. Melting point: 182-183° C.

[0746] NMR ¹H (100 MHz, DMSO d6, δ): 6.80 (s, 2H, Ph); 6.74 (m, 4H,Ph—NR₂); 4.80 (m, 2H, NH₂); 3.91 (s, 6H, 2×OCH₃); 3.77 (m, 4H,piperazine); 3.08 (m, 4H, piperazine).

[0747] 11.3)N-{4-[4-[3,5-dimethoxy-4-hydroxybenzoyl]-1-piperazinyl]-phenyl}-2-thiophenecarboximidamideHydrochloride: 11

[0748] 0.32 g (1.13 mmole) of S-methyl-2-thiophenethiocarboximidehydriodide (Ann. Chim. (1962), 7, 303-337) is introduced into a 100 mlflask containing a solution of 0.4 g (1.13 mmole) of intermediate 11.2in 10 ml of 2-propanol. After heating at 50° C. for 15 hours, thereaction medium is concentrated to dryness under vacuum. The evaporationresidue is then taken up in 100 ml of an ethyl acetate/saturatedsolution of sodium carbonate mixture (1/1). A precipitate appears whichis filtered and rinsed successively with 20 ml of water, 20 ml of ethylacetate and 50 ml of ether. The base obtained is salified in thepresence of a molar solution of HCl in anhydrous diethyl ether. Afterfiltration, rinsing with 10 ml of acetone and drying, 0.12 g (20%) of apale yellow powder is obtained. Melting point: 184-185° C.

[0749] NMR ¹H (400 MHz, DMSO d6, δ): 11.47 (s, 1H, NH⁺); 9.78 (s, 1H,NH⁺); 8.76 (s, 1H, NH⁺); 8.18 (m, 2H, thiophene); 7.37 (m, 1H,thiophene); 7.28 (m, 4H, Ph—N); 6.74 (s, 2H, Ph); 4.27 (wide s, 1H, OH);3.80 (s, 6H, 2×OCH₃); 3.70 (m, 4H, piperazine); 3.33 (m, 4H,piperazine).

[0750] IR: ν_(OH): 3423 cm⁻¹; ν_(C═O) (amide): 1610 cm⁻¹; ν_(C═N)(amidine): 1587 cm⁻¹.

Example 12 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[(2-thienyl(imino)methyl)amino]phenyl}-2H-1-benzopyran-2-carboxamide Hydrochloride:12

[0751] 12.1)3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-nitrophenyl)-2H-1-benzopyran-2-carboxamide:

[0752] In a 100 ml flask, 1.62 g (10 mmoles) of 1.1′-carbonyl-diimidazolis added to a solution of 2.5 g (10 mmoles) of Trolox® in 25 ml of THF.After agitation at ambient temperature for one hour, a solution of4-nitroaniline in 20 ml of THF is added dropwise. Agitation is continuedfor 15 hours and the solvent is evaporated off under vacuum. The residueis diluted in 50 ml of dichloromethane and washed successively with 25ml of a molar solution of hydrochloric acid, 25 ml of water and 25 ml ofbrine. The organic phase is dried over sodium sulphate, filtered andconcentrated under reduced pressure. The oil obtained is purified on asilica gel column (eluant: petroleum ether (B.p. 40-70° C.)/ethylacetate: 7/3). After concentration of the pure fractions, a pale yellowpowder is obtained with a yield of 77%. Melting point: 150-151° C.

[0753] NMR ¹H (100 MHz, CDCl₃, δ): 8.68 (s, 1H, CONH); 7.91 (m, 4H, Ph);4.59 (s, 1H, OH); 2.95-0.87 (m, 16H, Trolox®).

[0754] 12.2)3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-aminophenyl)-2H-1-benzopyran-2-carboxamide:

[0755] The experimental protocol used is the same as that described forintermediate 9.2, with3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-nitrophenyl)-2H-1-benzopyran-2-carboxamidereplacing the2,6-bis-(1,1-dimethylethyl)-4-{[4-(4-nitrophenyl)-1-piperazinyl]-carbonyl}-phenol.The product of the reaction is purified on a silica gel column (eluant:petroleum ether (B.p. 40-70° C.)/ethyl acetate: 6/4). The pure fractionsare collected, after evaporation of the solvent under vacuum, acolourless oil is obtained with a yield of 45%.

[0756] NMR ¹H (100 MHz, CDCl₃, δ): 8.19 (s,1H, CONH); 7.00 (m, 4H, Ph);4.59 (s, 1H, OH); 3.65 (wide s, 2H, NH₂); 2.95-0.87 (m, 16H, Trolox®).

[0757] 12.3) 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-{4-[2-thienyl(iminomethyl)amino]phenyl}-2H-1-benzopyran-2-carboxamide Hydrochloride:12

[0758] The experimental protocol used is the same as that described forcompound 1, with3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-N-(4-aminophenyl)-2H-1-benzopyran-2-carboxamidereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide.Melting point: 279-280° C.

[0759] NMR ¹H (400 MHz, DMSO d6, δ): 9.80 (s, 1H, NH⁺); 9.50 (s, 1H,NH⁺); 8.73 (s, 1H, NHCO); 8.18 (m, 2H, thiophene); 7.60 (s, 1H, OH);7.59 (m, 4H, Ph); 7.36 (m, 1H, thiophene); 2.60-1.57 (m, 16H, Trolox®).

[0760] IR: ν_(OH): 3236 cm⁻¹; ν_(C═O) (amide): 1683 cm⁻¹; ν_(C═N)(amidine): 1577 cm⁻¹.

Example 13N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamideHydrochloride: 13

[0761] 13.1)3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol:

[0762] In a 100 ml flask, 1.62 g (10 mmoles) of1.1′-carbonyl-diimidazole is added to a solution of 2.5 g (10 mmoles) ofTrolox® in 25 ml of THF. After one hour of agitation at ambienttemperature, a solution of 1-(4-nitrophenyl)piperazine in 10 ml of DMFis added dropwise. Agitation is continued for 15 hours, the reactionmedium is then concentrated under vacuum. The evaporation residue isdissolved in 50 ml of dichloromethane and washed successively with 3×25ml of water and 25 ml of brine. The organic phase is dried over sodiumsulphate, filtered and concentrated under reduced pressure. The oilobtained is precipitated from 30 ml of a (95/5) ethyl acetate/methanolmixture, the solid is filtered out and washed with 2×20 ml of ethylacetate. A pale yellow powder is obtained with a yield of 79%. Meltingpoint: 199-200° C.

[0763] NMR ¹H (100 MHz, CDCl₃, δ): 7.45 (m, 4H, Ph); 4.41-3.35 (m, 8H,piperazine); 2.95-1.25 (m, 16H, Trolox®).

[0764] 13.2)3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol:

[0765] The experimental protocol used is the same as that described forintermediate 2.2, with3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-olreplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.The product of the reaction is purified on a silica gel column (eluant:dichloromethane/methanol: 9/1). The pure fractions are collected toproduce, after evaporation of the solvent under vacuum, a brown oil witha yield of 66%.

[0766] NMR ¹H (100 MHz, CDCl₃, δ): 6.70 (m, 4H, Ph); 4.15-2.97 (m, 8H,piperazine); 2.80-0.90 (m, 18H, Trolox®).

[0767] 13.3)N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamideHydrochloride: 13

[0768] The experimental protocol used is the same as that described forthe compound 1, with3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-olreplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-amino-phenyl)-benzamide.However, the reaction is slower and requires 15 hours of heating. Thebase obtained after extraction is purified on a silica gel column(eluant: petroleum ether (B.p. 40-70° C.)/ethyl acetate: 3/7). The purefractions are concentrated under vacuum and the evaporation residue issalified in the presence of a molar solution of HCl in anhydrous diethylether. A yellow powder pale is obtained with a yield of 40%. Meltingpoint: 210-211° C.

[0769] NMR ¹H (400 MHz, DMSO d6, δ): 11.50 (s, 1H, NH⁺); 9.79 (s, 1H,NH⁺); 8.69 (s, 1H, NH⁺); 8.19 (m, 2H, thiophene); 7.38 (m, 1H,thiophene); 7.20 (m, 4H, Ph); 4.58 (wide s, 1H, OH); 4.11 (m, 2H,piperazine); 3.61 (m, 2H, piperazine); 3.19 (m, 4H, piperazine);2.62-1.55 (m, 16H, Trolox®).

[0770] IR: ν_(OH): 3410 cm^(−1,) ν_(C═O) (amide): 1642 cm^(−1;) ν_(C═N)(amidine): 1613 cm⁻¹.

Example 14 N-{4-[4-[(5methoxy-1H-indol-3-yl)methylcarbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide:14

[0771] 14.1)1-[(5-methoxy-1H-indol-3-yl)methylcarbonyl]-4-(4-nitrophenyl)-piperazine:

[0772] In a 100 ml flask, 1.62 g (10 mmoles) of1.1′-carbonyl-diimidazole is added to a solution of 2.05 g (10 mmoles)of 5-methoxyindole-3-acetic acid in 10 ml of THF. After one hour ofagitation at ambient temperature, a solution of1-(4-nitrophenyl)piperazine in 10 ml of DMF is added dropwise. Agitationis continued for 15 hours. The reaction medium is then concentratedunder vacuum and the evaporation residue is precipitated from 50 ml ofan ethyl acetate/water mixture (1/1). After filtration, the solid isrinsed successively with 50 ml of water, 50 ml of ethyl acetate and 50ml of dichloromethane. After drying under vacuum, a yellow powder isobtained with a yield of 91%. Melting point: 239-240° C.

[0773] NMR ¹H (100 MHz, DMSO d6, δ): 10.90 (m, 1H, NH); 7.63 (m, 4H,Ph—NO₂); 7.40-7.15 (m, 3H, indol); 6.87 (dd, 1H indol, J_(otho)=8.7 Hz,J_(meta)=2.8 Hz); 3.90 (s, 2H, CH₂—CO); 3.88 (s, 3H, OCH₃); 3.79 (m, 4H,piperazine); 3.50 (m, 4H, piperazine).

[0774] 14.2) 1-[(5methoxy-1H-indol-3-yl)methylcarbonyl]-4-(4-aminophenyl)piperazine:

[0775] In a 250 ml Parr flask, 1 g (2.53 mmoles) of intermediate 14.1 isdissolved in 30 ml of DMSO in the presence of 10%Pd/C. The mixture isagitated under 20 PSI of hydrogen, at 25° C., for 7 hours. Afterfiltration on celite, the filtrate is concentrated under vacuum. Theevaporation residue is diluted in 50 ml of ethyl acetate and washed with3×50 ml of water. The organic phase is then extracted with 2×25 ml of amolar solution of HCl. After the acid solution is washed with 2×25 ml ofethyl acetate, it is alkalinized using sodium carbonate in powder form.Once the product is re-extracted using 2×50 ml of ethyl acetate, theorganic solution is dried over sodium sulphate, filtered and the solventis evaporated off under vacuum. The residue is purified on a silica gelcolumn (eluant: dichloromethane/methanol: 98/2). The pure fractions arecollected and after evaporation of the solvent under reduced pressure,0.39 g of a pale yellow powder is obtained with a yield of 46%. Meltingpoint: 119-120° C.

[0776] NMR ¹H (100 MHz, CDCl₃, δ): 8.32 (s, 1H, indolic NH); 7.27-6.80(m, 4H, indole); 6.69 (m, 4H, Ph—NH₂); 3.82 (s, 3H, OCH₃); 3.80 (s, 2H,CH₂—CO); 3.80 (m, 2H, piperazine); 3.62 (m, 2H, piperazine); 3.48 (s,2H, NH₂); 2.90 (m, 4H, piperazine).

[0777] 14.3) N-{4-[4-[(5methoxy-1H-indole-3-yl)methylcarbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamide:14

[0778] The experimental protocol used is the same as that described forthe compound 1, with 1-[(5methoxy-1H-indole-3-yl)methylcarbonyl]-4-(4-aminophenyl)-piperazinereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Theexpected product is isolated in the form of the free base with a yieldof 20% (pale yellow powder). Melting point: 221-222° C.

[0779] NMR ¹H (400 MHz, DMSO d6, δ): 10.78 (s, 1H, indolic NH); 7.72 (m,1H, thiophene); 7.59 (m, 1H, thiophene); 7.22 (d, 1H, indole, J=8.7 Hz);7.19 (m, 1H, thiophene); 7.09 (m, 2H, indole); 6.82 (m, 4H, Ph); 6.72(m, 1H indole); 6.35 (s, 2H, NH₂); 3.80 (s, 2H, CH₂); 3.73 (s, 3H, CH₃);3.62 (m, 4H, piperazine); 2.95 (m, 4H, piperazine).

[0780] IR: ν_(OH): 3414 cm^(−1;) ν_(C═O) (amide): 1628 cm^(−1,) ν_(C═N)(amidine): 1590 cm⁻¹.

Example 15N-[4-[4-[{3-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-oxo-2-propenyl}-1-piperazinyl]-phenyl]]-2-thiophenecarboximidamideFumarate: 15

[0781] 15.1)2,6-bis-(1,1-dimethylethyl)-4-[3-[4-(4-nitrophenyl)-1-piperazinyl]-3-oxo-2-propenyl}-phenol:

[0782] The experimental protocol used is the same as that described forintermediate 11.1, with 3,5-di-tert-butyl-4-hydroxycinnamic acidreplacing the syringic acid. An oil is obtained with a yield of 60%.

[0783] NMR ¹H (100 MHz, CDCl₃, δ): 7.71 (d, 1H, C═CH, J=15.0 Hz); 7.51(m, 4H, Ph—NO₂); 7.38 (s, 2H, Ph); 6.69 (d, 1H, HC═C, J=15.0 Hz); 5.50(s, 1H, OH); 3.88 (m, 4H, piperazine); 3.53 (m, 4H, piperazine); 1.47(s, 18H, 2×tBu).

[0784] 15.2)2,6-bis-(1,1-dimethylethyl)-4-{3-[4-(4-aminophenyl)-1-piperazinyl]-3-oxo-2-propenyl}-phenol:

[0785] In a 50 ml flask equipped with a refrigerant, 0.5 g (1 mmole) ofintermediate 15.1 is dissolved in 5 ml of concentrated hydrochloric acidand 5 ml of absolute ethanol. The mixture is cooled down to 0° C. and1.69 g (7.5 mmoles) of tin chloride (dihydrate) is added in severalportions. After this addition, the reaction medium is heated underreflux for 30 minutes. The solvents are then evaporated off undervacuum, the residue is taken up in 15 ml of water, neutralized with 2Nsoda and diluted with 20 ml of dichloromethane. The precipitate obtainedis filtered on celite and the filtrate is decanted. The organic phase isdried over sodium sulphate, filtered and concentrated under reducedpressure to produce 0.3 g (67%) of a yellow oil.

[0786] NMR ¹H (100 MHz, CDCl₃, δ): 7.66 (d, 1H, C═CH, J=15.0 Hz); 7.37(s, 2H, Ph); 6.75 (m, 4H, Ph—NH₂); 6.30 (d, 1H, HC═C, J=15.0 Hz); 5.46(s, 1H, OH); 3.80 (m, 4H, piperazine); 3.06 (m, 4H, piperazine); 1.46(s, 18H, 2×tBu).

[0787] 15.3)N-[4-[4-[(3-[3,5-bis-(1,1-dimethylethyl)-4-hydroxy-phenyl]-1-oxo-2-propenyl}-1-piperazinyl]-phenyl]]-2-thiophenecarboximidamideFumarate: 15

[0788] The experimental protocol used is the same as that described forcompound 1, with2,6-bis-(1,1-dimethylethyl)-4-{3-[4-(4-aminophenyl)-1-piperazinyl]-3-oxo-2-propenyl}-phenolreplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide.

[0789] The product of the reaction is salified in the presence of anequimolar quantity of fumaric acid in ethanol under reflux. Compound 15is obtained in the form of a yellow powder with a yield of 22%. Meltingpoint: 170.5-173° C.

[0790] NMR ¹H (400 MHz, DMSO d6, δ): 7.77 (s, 1H, thiophene); 7.67 (d,1H, thiophene, J=5.0 Hz); 7.48 (d, 1H, C═CH, J=15.0 Hz); 7.39 (s, 2H,Ph); 7.34 (wide s, 1H, OH); 7.13 (t, 1H, thiophene, J=4.0 Hz); 7.05 (d,1H, HC═C, J=15.0 Hz); 6.92 (m, 4H, Ph—N); 6.60 (s, 2H, CH═CH fumarate);3.78 (m, 4H, piperazine); 3.13 (m, 4H, piperazine); 1.41 (s, 18H.2×tBu).

[0791] IR: ν_(OH): 3619 cm⁻¹, 3300 cm⁻¹; ν_(C═O) (amide): 1640 cm^(−1,)ν_(C═C): 1600 cm⁻¹; ν_(C═N) (amidine): 1570 cm⁻¹.

Example 163,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{3-[[(2-thienyl(imino)methyl)amino]phenyl]methyl}-benzamideHydrochloride: 16

[0792] 16.1)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-nitrophenyl)methyl]-benzamide:

[0793] The experimental protocol used is the same as that described forintermediate 2.1, with 3-nitrobenzylamine hydrochloride replacing the4-nitrobenzylamine hydrochloride. A white powder is obtained with ayield of 63%. Melting point: 210-211° C.

[0794] NMR ¹H (100 MHz, DMSO, δ): 9.12 (m, 1H, NH); 8.25 (m, 2H,Ph—NO₂); 7.80 (m, 4H, Ph—NO₂+Ph—OH); 7.60 (wide s, 1H, OH); 4.68 (d, 2H,CH₂, J=6 Hz); 1.55 (s, 18H, 2×tBu).

[0795] 16.2)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-aminophenyl)methyl]-benzamide:

[0796] In a 250 ml Parr flask, 2.40 g (6.2 mmoles) of3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-nitrophenyl)methyl]-benzamideis dissolved in 45 ml of an absolute ethanol/THF mixture (1/2) in thepresence of 10% Pd/C. The mixture is agitated under 20 PSI of hydrogen,at 30° C., for three hours. After filtration on celite, the filtrate isconcentrated to dryness and the residue is purified on a silica column(eluant: heptane/ethyl acetate: 60/40). The pure fractions are collectedand concentrated under reduced pressure to produce 0.94 g (45%) of awhite powder. Melting point: 171-172° C.

[0797] NMR ¹H (100 MHz, CDCl₃, δ): 7.20 (m, 2H, Ph—NH₂); 6.70 (m, 4H,Ph—NH₂+Ph—OH); 6.34 (m, 1H, NH); 5.55 (s, 1H, OH); 4.56 (d, 2H, CH₂, J=6Hz); 3.70 (wide s, 2H, NH₂); 1.49 (s, 18H, 2×tBu).

[0798] 16.3)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(3-[[(2-thienyl-(imino)methyl)amino]phenyl]methyl}-benzamideHydrochloride: 16

[0799] The experimental protocol used is the same as that described forcompound 1, with3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(3-aminophenyl)methyl]-benzamidereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Aftersalification with a molar solution of HCl in an acetone/anhydrousmethanol mixture, a pale yellow powder is obtained with a yield of 50%.Melting point: 226-227° C.

[0800] NMR ¹H (400 MHz, DMSO d6, δ): 11.71 (s, 1H, NH⁺); 9.93 (s, 1H,NH⁺); 9.10 (s, 1H, CONH); 9.00 (s, 1H, NH⁺); 8.18 (m, 2H, thiophene);7.70 (s, 2H, Ph); 7.42 (m, 6H, thiophene, Ph—NH, OH); 4.50 (d, 2H, CH₂—NHCO, J=5.4 Hz); 1.40 (s, 18H, 2×tBu).

[0801] IR: ν_(OH): 3420 cm^(−1;) ν_(C═O) (amide): 1639 cm^(−1,) ν_(C═N)(amidine): 1578 cm⁻¹.

Example 17N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-ureaHydrochloride: 17

[0802] 17.1) 4-amino-2,6-bis-(1,1-dimethylethyl)-phenol:

[0803] In a 250 ml Parr flask, 3.6 g (14 mmoles) of4-nitro-2,6-bis-(1,1-dimethylethyl)phenol (J. Org. Chem. (1968), 33 (1),223-226) is dissolved in 60 ml of a (2/1) mixture of ethanol anddichloromethane in the presence of a catalytic quantity of 10% Pd/C. Themixture is agitated for 2 hours, at 20° C., under 20 PSI of hydrogen.After filtration on celite, the filtrate is concentrated to drynessunder reduced pressure. The reddish-brown powder obtained is suspendedin heptane (30 ml), filtered and rinsed with the same volume of heptane.The expected product is obtained in the form of an salmon pink powderwith a yield of 50% (1.56 g). Melting point: 123-124° C.

[0804] NMR ¹H (100 MHz, CDCl₃, δ): 6.60 (s, 2H, Ph); 4.65 (wide s, 1H,OH); 3.15 (wide s, 2H, NH₂); 1.42 (s, 18H, 2×tBu).

[0805] 17.2) 4-nitrophenylacetic Acid Chloride:

[0806] 3.75 ml (7.5 mmoles) of a 2M solution of oxalyl chloride indichloromethane is added at 20° C. to a solution of 0.9 g (5 mmoles) of4-nitrophenylacetic acid in a mixture composed of 10 ml ofdichloromethane and 0.5 ml of DMF. After agitation for 30 minutes, thesolution is concentrated under vacuum. The yellow oil obtained is usedwithout additional purification in the following stage.

[0807] 17.3) 4-nitrobenzylisocyanate:

[0808] The chloride of 4-nitrophenylacetic acid in solution in dryacetone (7.5 ml) is slowly added to an aqueous solution of 0.75 g (11.5mmoles) of sodium azide, cooled down to 0° C. Agitation of the medium ismaintained for one hour after the addition is completed, at 0-5° C. Thereaction medium is then diluted with 30 ml of chloroform, decanted andthe organic phase washed with water (20 ml) followed by a saturatedsolution of sodium chloride (20 ml). After drying over sodium sulphate,the organic solution is filtered and partly concentrated (

20 ml) under vacuum. This solution of the acylazide in chloroform isthen heated, under reflux, for one hour. The isocyanate obtained is useddirectly, in solution, in the following stage.

[0809] 17.4)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)methyl]-urea:

[0810] 1.1 g (5 mmoles) of 4-amino-2,6-bis-(1,1-dimethylethyl)-phenol isadded in one portion to the isocyanate solution (intermediate 17.3)(theoretically 5 mmoles) in 20 ml of chloroform. After agitation for 2hours at 20° C., the precipitate which appears is filtered out andrinsed with chloroform (2×20 ml). A yellow powder is obtained with ayield of 72%. Melting point: 240-241° C.

[0811] NMR ¹H (100 MHz, DMSO d6, δ): 8.60 (s, 1H, NH—Ph); 8.01 (m, 4H,Ph—NO₂); 7.30 (s, 2H, Ph—OH); 6.77 (m, 1H, NH—CH₂); 6.71 (s, 1H, OH);4.52 (d, 2H, CH₂, J=5.5 Hz); 1.49 (s, 18H, 2×tBu).

[0812] 17.5)N-[(4-aminophenyl)methyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea:

[0813] In a 100 ml autoclave, 0.55 g (1.38 mmole) ofN-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)methyl]-ureais dissolved in a 2/1 mixture of ethanol and ethyl acetate, in thepresence of 10% Pd/C. After hydrogenation for one and a half hours at20° C., under 20 PSI, the mixture is filtered on celite and the filtrateis concentrated under vacuum. The evaporation residue is diluted in 20ml of diethyl ether and the expected product crystallizes spontaneously.The crystals are filtered out and rinsed with 20 ml of diethyl ether. Awhite powder is obtained with a yield of 60% (0.31 g). Melting point:194-195° C.

[0814] NMR ¹H (100 MHz, CDCl₃, δ): 7.08 (s, 2H, Ph—OH); 6.87 (m, 4H,Ph—NH₂); 6.15 (s, 1H, NH—Ph); 5.14 (s, 1H, OH); 4.89 (m, 1H, NH—CH₂);4.41 (d, 2H, CH₂, J=5.5 Hz); 3.65 (wide s, 2H, NH₂); 1.40 (s, 18H,2×tBu).

[0815] 17.6)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[2-thienyl(iminomethyl)amino]phenyl}methyl}-ureaHydrochloride: 17

[0816] The experimental protocol used is the same as that described forcompound 1, withN-[(4-aminophenyl)methyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-ureareplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Aftersalification with a molar solution of HCl in anhydrous diethyl ether, awhite powder is obtained with a yield of 45%. Melting point: 236-237° C.

[0817] NMR ¹H (400 MHz, DMSO d6, δ): 11.42 (wide s, 1H, NH⁺); 9.77 (wides, 1H, NH⁺); 8.92 (wide s, 1H, NH⁺); 8.54 (s, 1H, NH—Ph); 8.11 (m, 2H,thiophene); 7.41 (m, 5H, Ph—N, thiophene); 7.19 (s, 2H, Ph); 6.70 (m,1H, NH—CH₂); 6.60 (s, 1H, OH); 4.35 (d, 2H, CH₂, J=5.5 Hz); 1.34 (s,18H, 2×tBu).

[0818] IR: ν_(OH): 3624 cm⁻¹; ν_(C═O) (urea): 1644 cm^(−1;) ν_(C═N)(amidine): 1569 cm⁻¹.

Example 18N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}-amino]-2-hydroxyphenyl]-2-thiophenecarboximidamideHydrochloride: 18

[0819] 18.1)3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-nitrophenyl)-2-propenamide:

[0820] 1.78 g (6.4 mmoles) of 3,5-di-tert-butyl-4-hydroxycinnamic acid,0.99 g (6.4 mmoles) of 4-amino-2-nitrophenol, previously diluted in 10ml of DMF, 0.86 g (6.4 mmoles) of hydroxybenzotriazol and 1.32 g (6.4mmoles) of dicyclohexylcarbodiimide are introduced into a 50 ml flaskcontaining 10 ml of THF. The reaction medium is agitated for 15 hours atambient temperature, the precipitate which appears is filtered andrinsed with ethyl acetate. After concentration of the solution underreduced pressure, the residue is diluted in 20 ml of ethyl acetate andthe insoluble part is filtered again. The filtrate is washed with 20 mlof a saturated solution of sodium carbonate followed by 20 ml of waterand 20 ml of a saturated solution of sodium chloride. After drying oversodium sulphate, the organic solution is filtered and concentrated todryness under reduced pressure. The residue is purified on a silicacolumn (eluant: heptane/ethyl acetate: 8/2). The pure fractions arecollected and concentrated under vacuum to produce 1.95 g (47%) of theexpected compound in the form of a yellow-orange powder. Melting point:231-232° C.

[0821] NMR ¹H (100 MHz, CDCl₃, δ): 10.45 (s, 1H, NH); 8.45 (d, 1H,Ph—NO₂, J=1.7 Hz); 7.98 (dd, 1H, Ph—NO₂, J=1.7 Hz and J=6.8 Hz); 7.78(d, 1H, —CH═CH—, J=10.5 Hz); 7.75 (s, 1H, OH); 7.40 (s, 2H, Ph—OH); 7.20(d, 1H, Ph—NO₂); 6.48 (d, 1H, —CH═CH—); 5.51 (s, 1H, OH); 1.50 (s, 18H,2×tBu).

[0822] 18.2)3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-aminophenyl)-2-propenamide:

[0823] In a 100 ml flask equipped with a refrigerant, 0.9 g (2.18mmoles) of3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-nitrophenyl)-2-propenamideis dissolved in 20 ml of ethyl acetate, 2.46 g (10.9 mmoles) of tinchloride (dihydrate) is added and the mixture is heated at 70° C. forthree hours. After returning to ambient temperature, the reaction mediumis poured onto an agitated solution of sodium bicarbonate (0.1 M), aprecipitate forms, which is eliminated by filtration on celite. Thefiltrate is decanted and the aqueous phase is extracted with 20 ml ofethyl acetate. The organic phases are collected together and washed with20 ml of water followed by 20 ml of a saturated solution of sodiumchloride. After drying over sodium sulphate and filtration, the organicsolution is concentrated to dryness, under partial vacuum. Theevaporation residue is suspended in a heptane/ethyl acetate mixture(1/1) and filtered to produce a yellowish powder with a yield of 53%.The product is used as it is in the following stage.

[0824] 18.3)N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}amino]-2-hydroxyphenyl]-2-thiophenecarboximidamideHydrochloride: 18

[0825] The experimental protocol used is the same as that described forcompound 1, with3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-aminophenyl)-2-propenamidereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Thefree base is purified on a silica column (eluant: heptane/ethyl acetate:35/65). The pure fractions are collected and concentrated under reducedpressure. The evaporation residue is diluted in 10 ml of acetone andsalified with a molar solution of HCl in anhydrous ether, as describedpreviously. 0.35 g (62%) of a yellow powder is obtained. Melting point:199-200° C.

[0826] NMR ¹H (400 MHz, DMSO, δ): 11.11 (s, 1H, NH⁺); 10.29 (s, 1H,NH⁺); 10.17 (s, 1H, NH⁺); 9.71 (s, 1H, CONH); 8.61 (wide s, 1H, OH);8.14 (m, 2H, thiophene); 7.79 (s, 1H, Ph—N); 7.53 (m, 1H, Ph—N); 7.48(d, 1H, —CH═CH—, J=14.7 Hz); 7.37 (m, 4H, Ph-tBu+OH+Ph—N); 7.05 (m, 1H,thiophene); 6.68 (d, 1H, —CH═CH—); 1.41 (s, 18H, 2×tBu).

[0827] IR: ν_(OH): 3624 cm⁻¹, 3415 cm⁻¹; ν_(C═O) (amide): 1656 cm^(−1,)ν_(C═C): 1616 cm⁻¹; ν_(C═N) (amidine): 1587 cm⁻¹.

Example 19N-[3-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}-amino]-4-hydroxyphenyl]-2-thiophenecarboximidamideHydrochloride: 19

[0828] 19.1)3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-nitrophenyl)-2-propenamide:

[0829] The experimental protocol used is the same as that described forintermediate 18.1, with 2-amino-4-nitrophenol replacing the4-amino-2-nitrophenol. A light yellow powder is obtained with a yield of25%. Melting point: 256-257° C.

[0830] NMR ¹H (400 MHz, DMSO, δ): 11.79 (wide s, 1H, OH); 9.59 (s, 1H,NH); 9.21 (wide s, 1H, Ph—NO,); 7.90 (badly resolved dd, 1H, Ph—NO₂,J=8.1 Hz); 7.52 (d, 1H, —CH═CH—, J=15.5 Hz); 7.47 (s, 1H, OH); 7.42 (s,2H, Ph—OH); 7.15 (d, 1H, —CH═CH—); 7.04 (d, 1H, Ph—NO₂); 1.42 (s, 18H,2×tBu).

[0831] 19.2)3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-aminophenyl)-2-propenamide:

[0832] The experimental protocol used is the same as that described forintermediate 18.2, with3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-nitrophenyl)-2-propenamidereplacing the3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-nitrophenyl)-2-propenamide.A yellow powder is obtained with a yield of 74%. The product is usedwithout additional purification in the following stage.

[0833] 19.3)N-[5-[{3-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-2-propenyl}-amino]-2-hydroxyphenyl]-2-thiophenecarboximidamideHydrochloride: 19

[0834] The experimental protocol used is the same as that described forcompound 1, with3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(2-hydroxy-5-aminophenyl)-2-propenamidereplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Aftersalification with a molar solution of HCl in anhydrous diethyl ether, ayellow powder is obtained with a yield of 54%. Melting point: 256-257°C.

[0835] NMR ¹H (400 MHz, DMSO d6, δ): 11.32 (s, 1H, NH⁺); 10.67 (s, 1H,NH⁺); 9.69 (s, 1H, NH⁺); 9.55 (s, 1H, CONH); 8.70 (wide s, 1H, OH); 8.19(m, 2H, thiophene); 7.48 (d, 1H, —CH═CH—, J=15.5 Hz); 7.40 (s, 2H,Ph-tBu); 7.37 (m, 2H, Ph—N); 7.34 (s, 1H, OH); 7.13 (d, 1H, —CH═CH—);7.10 (m, 1H, Ph—N); 6.99 (m, 1H, thiophene); 1.41 (s, 18H, 2×tBu).

[0836] IR: ν_(OH): 3623 cm⁻¹, 3410 cm⁻¹; ν_(C═O) (amide): 1652 cm^(−1,)ν_(C═C): 1616 cm⁻¹; ν_(C═N) (amidine): 1587 cm⁻¹.

Example 20N-{4-[4-[3,4,5-trihydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamideHydrochloride: 20

[0837] 20.1)5-{[4-(4-nitrophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triol:

[0838] The experimental protocol is the same as that described forintermediate 8.1, with 1-(4-nitrophenyl)piperazine replacing the4-nitrophenetylamine. A yellow powder still containing traces ofimpurities is obtained with a yield of 43%.

[0839] NMR ¹H (100 MHz, DMSO, δ): 9.17 (wide s, 2H, 2×-OH); 8.55 (wides, 1H, —OH); 7.57 (m, 4H, Ph—NO₂); 6.40 (s, 2H, Ph—OH); 3.59 (badlyresolved m, 8H, piperazine).

[0840] 20.2)5-{[4-(4-aminophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triol:

[0841] The experimental protocol used is the same as that described forintermediate 2.2, with5-{[4-(4-nitrophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triolreplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.A beige powder is obtained with a yield of 61%. This is used directly inthe following stage without additional purification.

[0842] NMR ¹H (100 MHz, DMSO, δ): 9.12 (wide s, 2H, 2×-OH); 8.55 (wides, 1H, —OH); 6.61 (m, 4H, Ph—NH₂); 6.34 (s, 2H, Ph—OH); 3.59 (m, 4H,piperazine); 2.89 (m, 4H, piperazine).

[0843] 20.3)N-{4-[4-[3,4,5-trihydroxybenzoyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamideHydrochloride: 20

[0844] The experimental protocol used is the same as that described forcompound 1, with5-{[4-(4-aminophenyl)-1-piperazinyl]carbonyl}-benzene-1,2,3-triolreplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Aftertreatment with a molar solution of HCl in anhydrous diethyl ether, abrown powder is obtained with a yield of 25%. Melting point: 198-205° C.

[0845] NMR ¹H (400 MHz, DMSO d6, δ): 11.38 (s, 1H, NH⁺); 9.75 (s, 1H,NH⁺); 9.00 (wide s, 1H, OH); 8.75 (s, 1H, NH⁺); 8.15 (m, 2H, thiophene);7.39 (m, 1H, thiophene); 7.22 (m, 4H, Ph—N); 6.40 (s, 2H, Ph); 5.11(wide s, 2H, 2×OH); 3.65 (m, 4H, piperazine); 3.29 (m, 4H, piperazine).

[0846] IR: ν_(OH): 3399 cm^(−1;) ν_(C═O) (amide): 1696 cm^(−1;) ν_(C═N)(amidine): 1588 cm⁻¹.

Example 21N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl)carbonylamino}-urea Hydrochloride: 21

[0847] 21.1)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)carbonylamino]-urea:

[0848] 0.22 g (0.73 mmole) of triphosgene at 20° C. is dissolved in a 50ml three-necked flask equipped with an addition funnel, under an argonatmosphere. Over one hour, a solution of 0.44 g (2 mmoles) of4-amino-2,6-bis-(1,1-dimethylethyl)-phenol (intermediate 17.1) and 0.38ml (2.2 mmoles) of diisopropylethylamine in 7 ml of anhydrousdichloromethane is added dropwise to this mixture. Five minutes afterthe end of this addition, a solution of 0.36 g (2 mmoles) of4-nitrobenzoyl-hydrazide and 0.38 ml (2.2 mmoles) ofdiisopropylethylamine in 4 ml of anhydrous DMF is added in a singleportion. After agitation for four hours at 20° C., the reaction mediumis concentrated to dryness under reduced pressure. The evaporationresidue is diluted in 40 ml of ethyl acetate and the organic solution iswashed successively with 3 times 20 ml of water and 20 ml of a saturatedsolution of sodium chloride. After drying over sodium sulphate, theorganic solution is filtered and the filtrate concentrated to drynessunder reduced pressure. The residue obtained is suspended in heptane,agitated and filtered to produce a yellow powder with a yield of 86%.Melting point: 163-164° C.

[0849] NMR ¹H (100 MHz, DMSO d6, δ): 10.65 (wide s, 1H, NH amide); 8.72(s, 1H, NH—Ph); 8.38 (m, 4H, Ph—NO₂); 8.20 (s, 1H, CO—NH—NH); 7.36 (s,2H, Ph—OH); 6.78 (s, 1H, OH); 1.50 (s, 18H, 2×tBu).

[0850] 21.2)N-[(4-aminophenyl)carbonylamino]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea:

[0851] In a 250 ml Parr flask, 0.72 g (1.68 mmoles) ofN-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)carbonylamino]-ureais dissolved in 30 ml of absolute ethanol in the presence of 10% Pd/C.The mixture is agitated under 20 PSI of hydrogen, at 30° C., for twohours. After filtration on celite, the filtrate is concentrated undervacuum. The evaporation residue is suspended in diethyl ether (20 ml),agitated and filtered to produce a pale yellow powder with a yield of75%. Melting point: 245-246° C.

[0852] NMR ¹H (100 MHz, DMSO d6, δ): 9.84 (wide s, 1H, NH amide); 8.56(s, 1H, NH—Ph); 7.85 (m, 2H, Ph—NH₂); 7.74 (s, 1H, CO—NH—NH); 7.38 (s,2H, Ph—OH); 6.78 (s, 1H, OH); 6.60 (m, 2H, Ph—NH₂); 5.80 (wide s, 2H,NH₂); 1.50 (s, 18H, 2×tBu).

[0853] 21.3)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{(4-[(2-thienyl(imino)methyl)amino]phenyl}carbonylamino}-ureaHydrochloride: 21

[0854] The experimental protocol used is the same as that described forcompound 1, with N-[(4-aminophenyl)carbonylamino]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxy phenyl]-ureareplacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)benzamide. Thefree base is purified on a silica column (eluant: heptane/ethyl acetate:1/1). The pure fractions are collected and concentrated under reducedpressure. The evaporation residue is diluted in 15 ml of acetone andsalified with a molar solution of HCl in anhydrous ether, as describedpreviously. 0.40 g (58%) of a yellow powder is obtained. Melting point:254-255° C.

[0855] NMR ¹H (400 MHz, DMSO, δ): 11.68 (wide s, 1H, NH⁺); 10.32 (s, 1H,NH amide); 9.94 (wide s, 1H, NH⁺); 9.13 (wide s, 1H, NH⁺); 8.68 (s, 1H,NH—CO); 8.18 (m, 2H, thiophene); 8.07 (m, 3H, CO—NH—NH+Ph—NH); 7.58 (m,2H, Ph—NH); 7.39 (m, 1H, thiophene); 7.22 (s, 2H, Ph—OH); 6.60 (s, 1H,OH); 1.36 (s, 18H, 2×tBu).

[0856] IR: ν_(OH): 3627 cm⁻¹; ν_(C═O) (amide), ν_(C═O) (urea): 1654cm⁻¹, 1602 cm^(−1,) ν_(C═N) (amidine): 1559 cm⁻¹.

Example 22N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-thioureaHydrochloride: 22

[0857] 22.1)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)methyl]-thiourea:

[0858] Compound 22.1 is obtained by the action of Lawesson's reagent onintermediate 17.4 according to an experimental protocol described in theliterature (J. Med. Chem. (1995), 38 (18), 3558-3565). A light yellowpowder is obtained with a yield of 80%. Melting point: 218-220° C.

[0859] NMR ¹H (100 MHz, CDCl₃, δ): 7.85 (m, 4H, Ph—NO₂); 7.70 (s, 1H,NH—Ph); 7.05 (s, 2H, Ph—OH); 6.21 (m, 1H, NH—CH₂); 5.40 (s, 1H, OH);5.00 (d, 2H, CH₂, J=6.5 Hz); 1.41 (s, 18H, 2×tBu).

[0860] 22.2)N-[(4-aminophenyl)methyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-thiourea:

[0861] The experimental protocol used is the same as that described forintermediate 18.2, with intermediate 22.1 replacing the3-[(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-(4-hydroxy-3-nitrophenyl)-2-propenamide.A beige powder is obtained with a yield of 70%. Melting point: 167-169°C.

[0862] NMR ¹H (100 MHz, CDCl₃, δ): 7.48 (wide s, 1H, NH—Ph); 6.95 (s,2H, Ph—OH); 6.81 (m, 4H, Ph—NH₂); 5.98 (m, 1H, NH—CH₂); 5.28 (s, 1H,OH); 4.69 (d, 2H, CH₂, J=5.5 Hz); 3.62 (wide s, 2H, NH₂); 1.40 (s, 18H,2×tBu).

[0863] 22.3)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{{4-[(2-thienyl(imino)methyl)amino]phenyl}methyl}-thioureaHydrochloride: 22

[0864] The experimental protocol used is the same as that described forintermediate 17.6, with intermediate 22.2 replacing theN-[(4-aminophenyl)methyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea.A pale yellow powder is obtained with a yield of 15%. Melting point:203-205° C.

[0865] NMR ¹H (400 MHz, DMSO d6, δ): 11.52 (wide s, 1H, NH⁺); 9.86 (wides, 1H, NH⁺); 8.98 (wide s, 1H, NH⁺); 8.39 (s, 1H, NH—Ph); 8.16 (m, 2H,thiophene); 7.46 (m, 6H, Ph—N, thiophene, NH—CH₂); 7.18 (s, 2H, Ph);6.92 (s, 1H, OH); 4.80 (wide s, 2H, CH₂); 1.35 (s, 18H, 2×tBu).

[0866] IR: ν_(OH): 3630 cm⁻¹; ν_(C═O) (urea): 1649 cm^(−1,) ν_(C═N)(amidine): 1600 cm⁻¹.

Example 23N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl}-ureaHydrochloride: 23

[0867] 23.1)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[2-(4-nitrophenyl)ethyl]-urea:

[0868] The experimental protocol used is the same as that described forintermediate 21.1, with 4-nitrophenetylamine replacing the4-nitrobenzoyl-hydrazide. A beige powder is obtained with a yield of80%. Melting point: 185-187° C.

[0869] NMR ¹H (100 MHz, CDCl₃, δ): 7.75 (m, 4H, Ph—NO₂); 7.00 (s, 2H,Ph—OH); 6.05 (s, 1H, OH); 5.18 (s, 1H, NH); 4.68 (m, 1H, NH—CH₂); 3.50(m, 2H, NH—CH ₂); 2.92 (m, 2H, CH₂); 1.40 (s, 18H, 2×tBu).

[0870] 23.2)N-[2-(4-aminophenyl)ethyl]-N′-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-urea:

[0871] The experimental protocol used is the same as that described forintermediate 21.2, with intermediate 23.1 replacing theN-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)-carbonylamino]-urea.A white powder is obtained with a yield of 56%. Melting point: 192-194°C.

[0872] NMR ¹H (100 MHz, DMSO d6, δ): 8.25 (wide s, 1H, Ph—NH—CO); 7.22(s, 2H, Ph—OH); 6.79 (m, 4H, Ph—NH₂); 6.65 (s, 1H, OH); 5.92 (m, 1H,NH—CH₂); 4.98 (wide s, 2H, —NH₂); 3.31 (m, 2H, NH—CH ₂); 2.65 (m, 2H,CH₂); 1.48 (s, 18H, 2×tBu).

[0873] 23.3)N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-{2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl}-ureaHydrochloride: 23

[0874] The experimental protocol used is the same as that described forcompound 1, with intermediate 23.2 replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Thefree base is purified on a silica column (eluant: heptane/ethyl acetate:1/1). The pure fractions are collected and concentrated under reducedpressure. The evaporation residue is diluted in 15 ml of acetone andsalified with a molar solution of HCl in anhydrous ether, as describedpreviously. Finally, 0.25 g (24%) of a pale yellow powder is obtained.Melting point: 207-210° C.

[0875] NMR ¹H (400 MHz, DMSO d6, δ): 11.48 (wide s, 1H, NH⁺); 9.83 (wides, 1H, NH⁺); 8.95 (wide s, 1H, NH⁺); 8.50 (s, 1H, NH—CO); 8.18 (m, 2H,thiophene); 7.38 (m, 5H, Ph—NH+thiophene); 7.18 (s, 2H, Ph—OH); 6.55 (s,1H, OH); 6.21 (m, 1H, CO—NH—CH₂); 3.35 (m, 2H, NH—CH ₂); 2.78 (m, 2H,CH₂); 1.36 (s, 18H, 2×tBu).

[0876] IR: ν_(OH): 3631 cm⁻¹; ν_(C═O) (urea): 1654 cm⁻¹, 1600 cm^(−1,)ν_(C═N) (amidine): 1560 cm⁻¹.

Example 24N-(4-{4-[(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl]phenyl)-2-thiophenecarboximidamideHydrochloride: 24

[0877] 24.1)1-{[3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl]carbonyl}-4-(4-nitrophenyl)piperazine:

[0878] The experimental protocol is identical to that described forintermediate 13.1, with(+)-3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxyliqueacid (prepared according to CHIMIA (1991), 45 (4), 121-3) replacing the(±)-Trolox®. A yellow powder is obtained.

[0879] NMR ¹H (100 MHz, CDCl₃, δ): 7.45 (m, 4H, Ph); 3.60 (s, 3H, CH₃O);3.40 (m, 4H, piperazine); 3.00 (m, 4H, piperazine); 2.50-1.60 (m, 16H,Trolox®).

[0880] 24.2)1-{[3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl]carbonyl}-4-(4-aminophenyl)piperazine:

[0881] The experimental protocol is identical to that described forintermediate 13.2, with intermediate 24.1 replacing the3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol.An oil is obtained which is used directly in the following stage.

[0882] NMR ¹H (100 MHz, CDCl₃, δ): 6.70 (m, 4H, Ph); 3.90 (wide d, 4H,piperazine); 3.60 (s, 3H, CH₃O); 3.45 (wide s, 2H, NH₂); 2.90 (m, 4H,piperazine); 2.60-1.60 (m, 18H, Trolox®).

[0883] 24.3)N-(4-{4-[(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1-piperazinyl}phenyl)-2-thiophenecarboximidamideHydrochloride: 24

[0884] The experimental protocol is the same as that described forcompound 13, with intermediate 24.2 replacing the3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol.A pale yellow powder is obtained. Melting point: 190-195° C.

[0885] NMR ¹H (400 MHz, DMSO, δ): 11.35 (wide s, 1H, NH⁺); 9.70 (wide s,1H, NH⁺); 8.70 (wide s, 1H, NH⁺); 8.15 (wide s, 2H, thiophene); 7.35(wide s, 1H, thiophene); 7.17 (m, 4H, Ph); 3.90 (wide d, 4H,piperazine); 3.50 (s, 3H, CH₃O); 3.15 (m, 4H, piperazine); 2.55-1.55 (m,16H, Trolox®).

[0886] IR: ν_(C═O) (amide): 1642 cm^(−1,) ν_(C═N) (amidine): 1618 cm⁻¹.

Example 25N-[4-{4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1H-1,4-diazepin-1-yl}phenyl]-2-thiophenecarboximidamideHydrochloride: 25

[0887] 25.1) hexahydro-4-(4-nitrophenyl)-1H-1,4-diazepine:

[0888] 3.37 g (24.4 mmoles) of potassium carbonate and 1.89 g (13.4mmoles) of 4-nitrofluorobenzene are added to a solution of 2.44 g (12.2mmoles) of (1,1-dimethyl) ethyl hexahydro-1H-1,4-diazepine-1-carboxylatein 50 ml of DMF. The reaction medium is heated at 100° C. for 16 hours.After cooling down, 25 ml of ethyl acetate and 50 ml of water are added.The organic solution is decanted and the aqueous phase extracted with 3times 50 ml of ethyl acetate. The organic phases are collected togetherand washed with 50 ml of brine, dried over sodium sulphate, filtered andconcentrated under vacuum. 3.7 g of a bright yellow solid is obtainedwith a yield of 95%. This solid is then dissolved in 100 ml of a mixtureof solvents (dichloromethane/ethyl acetate 1:1) to which 20 ml of a 6Naqueous solution of hydrochloric acid is added dropwise at 0° C. Aftervigorous agitation at 20° C. for 1 hour, the reaction medium isdecanted. The aqueous phase is basified to pH=11 with 4N soda andextracted with 3 times 50 ml of dichloromethane. The organic phases arecollected, washed with 50 ml of water followed by 50 ml of brine, driedover sodium sulphate and finally filtered and concentrated under vacuum.1.78 g of a bright yellow powder is obtained with a yield of 66%. Theproduct is used directly in the following stage without additionalpurification.

[0889] NMR ¹H (100 MHz, CDCl₃, δ): 8.10 (m, 2H, Ph); 6.65 (m, 2H, Ph);3.70 (q, 4H, CH₂N, J=5.2 Hz); 3.10 (t, 2H, CH₂N); 2.85 (t, 2H, CH₂N);1.95 (q, 2H, C—CH₂—C); 1.65 (wide s, 1H NH).

[0890] 25.2)1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]hexahydro-4-(4-nitrophenyl)-1H-1,4-diazepine:

[0891] In a 50 ml flask, 0.71 g (4.4 mmoles) of 1,1′-carbonyldiimidazoleis added to a solution of 1.07 g (4.3 mmoles) of (±)-Trolox® in 8 ml ofanhydrous THF. After agitation for one hour at 20° C., a solution of0.95 g (4.3 mmoles) of intermediate 25.1 in 4 ml of DMF is addeddropwise. The reaction medium is agitated for 16 hours at 20° C. Afterevaporation of the solvents under vacuum, the residue is taken up in 30ml of a mixture of solvents (dichloromethane/water 1:2). Afterdecanting, the organic phase is washed with 2 times 20 ml of water,dried over sodium sulphate and concentrated under vacuum. A pale yellowpowder is obtained with a gross yield of 97%. The product is useddirectly in the following stage without additional purification.

[0892] NMR ¹H (100 MHz, CDCl₃, δ): 8.10 (m, 2H, Ph); 6.60 (m, 2H, Ph);4.40 (wide s, 1H, OH); 3.50 (m, 8H, CH₂N); 2.50-1.50 (m, 18H,Trolox®+CH₂).

[0893] 25.3)1-(4-aminophenyl)-4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]hexahydro-1H-1,4-diazepine:

[0894] The experimental protocol used is the same as that described forintermediate 13.2, with intermediate 25.2 replacing the3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol.The product of the reaction is purified on a silica gel column (eluant:ethyl acetate/petroleum ether 3:2). An oil is obtained with a yield of57%.

[0895] 25.4)N-[4-{4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)carbonyl]-1H-1,4-diazepin-1-yl}phenyl]-2-thiophenecarboximidamideHydrochloride:

[0896] A mixture of 0.52 g (1.22 mmole) of intermediate 25.3 and 0.35 g(1.22 mmole) of S-methyl-2-thiophene thiocarboximide hydriodide in 4 mlof isopropanol is heated at 50° C. for 40 hours. The reaction medium isthen filtered and the solid obtained is taken up in 4 ml of a saturatedaqueous solution of sodium carbonate and 4 ml of ethyl acetate. Themixture is heated at 50° C. for 30 minutes, then decanted. The organicphase is washed twice with 10 ml of water followed by 10 ml of brine.The organic phases are collected, dried over sodium sulphate, filteredand concentrated under reduced pressure. The solid obtained is purifiedon a silica gel column (eluant: ethyl acetate/petroleum ether 5:1). 0.5g of product is obtained with a yield of 77%. 0.15 g (0.29 mmole) ofthis product is then dissolved in 2 ml of acetone. 0.84 ml (0.84 mmole)of a 1N hydrochloric acid solution in anhydrous ethyl ether is addeddropwise. The whole is agitated at ambient temperature for 30 minutes. Ayellow precipitate forms which is filtered. The precipitate istriturated and washed successively with 3 times 5 ml of ethyl ether and5 ml of acetone. The dark yellow powder is dried under vacuum at 70° C.for 48 hours. The yield obtained is 80%. Melting point: 180-185° C.

[0897] NMR ¹H (400 MHz, DMSO, δ): 11.15 (wide s, 1H, NH⁺); 9.60 (wide s,1H, NH⁺); 8.55 (wide s, 1H, NH⁺); 8.10 (wide s, 2H, thiophene); 7.35(wide s, 1H, thiophene); 7.02 (m, 4H, Ph); 4.80 (wide s, 1H, OH); 3.70(m, 8H, CH₂N); 2.50-1.40 (m, 18H, Trolox®+CH₂)—

[0898] IR: ν_(OH): 3412 cm^(−1,) ν_(C═O) (amide): 1613 cm^(−1,) ν_(C═N)(amidine): 1613 cm⁻¹.

Example 26(R)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamideHydrochloride: 26

[0899]

[0900] 26.1)(R)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]carbonyl}-2H-1-benzopyran-6-ol:

[0901] The experimental protocol used is the same as that described forcompound 13.1, with (R)-Trolox® replacing the (±)Trolox®. A brightyellow powder is obtained with a yield of 98%. Melting point: 102-105°C.

[0902] 26.2)(R)-3,4-dihydro-2,5,7,8-tetramethyl-2-(4-[(4-aminophenyl)-1-piperazinyl]carbonyl}-2H-1-benzopyran-6-ol:

[0903] The experimental protocol used is the same as that described forintermediate 2.2, with intermediate 26.1 replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.A pink powder is obtained with a yield of 75%. The product is used as itis in the following stage. Melting point: 103-105° C.

[0904] 26.3)(R)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamideHydrochloride: 26

[0905] The experimental protocol used is the same as that described forcompound 13, with intermediate 26.2 replacing the3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol.The product is obtained in the form of a pale yellow powder whichhydrates in air. Melting point: 195-197° C.

[0906] The NMR and IR analyses are identical to compound 13.

[0907] [α]_(D) ²⁰=43.5° (c=0.11; DMSO)

Example 27(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl]-2-thiophenecarboximidamideDihydrochloride: 27

[0908]

[0909] 27.1)(S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-nitrophenyl)-1-piperazinyl]carbonyl}-2H-1-benzopyran-6-ol:

[0910] The experimental protocol used is the same as that described forcompound 13.1, with (S)-Trolox® replacing the (±)Trolox®. A yellowpowder is obtained with a yield of 73%. Melting point: 110-111° C.

[0911] 27.2)(S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol:

[0912] The experimental protocol used is the same as that described forintermediate 2.2, with intermediate 27.1 replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)methyl]-benzamide.After purification on a silica gel column (heptane/ethyl acetate: 2/8),collection and evaporation under vacuum of the pure fractions, a beigepowder is obtained with a yield of 54%. Melting point: 109-111° C.

[0913] 27.3)(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamideDihydrochloride: 27

[0914] The experimental protocol used is the same as that described forcompound 13, with intermediate 27.2 replacing the3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol.The product is obtained in the form of a pale yellow powder whichhydrates in air. Melting point: 210.6-211.8° C.

[0915] The NMR and IR analyses are identical to compound 13.

[0916] [α]_(D) ²⁰=+76.2° (c=0.17; DMSO)

[0917] Alternatively, compound 27 can be prepared according to thefollowing protocol:

[0918] 27.4) methyl 2-thiophene Carboximidate:

[0919] 10.91 g (0.1 mole) of 2-thiophene carbonitrile, 100 ml ofanhydrous ethyl ether and 4.5 ml (0.11 mole) of methanol are introducedinto a 250 ml erlen meyer flask purged with argon. The solution iscooled down to 0° C. using an ice bath and saturated with a stream ofanhydrous gaseous HCl for 45 minutes. The reaction medium is agitatedfor an additional hour at 0° C. and overnight at 20° C. The precipitateformed is filtered out, washed with ethyl ether and dried. Thehydrochloride obtained is partitioned into a mixture of 100 ml of waterand 150 ml of ethyl ether. The medium is neutralized by adding 8.4 g(0.1 mole) of dry NaHCO₃. After decanting and separation, the organicphase is washed successively with 2×30 ml of water and 30 ml of brine.After drying over magnesium sulphate, the organic solution is filteredand concentrated under vacuum. A colourless oil is obtained with a yieldof 66%.

[0920] NMR ¹H (400 MHz, CDCl₃, δ): 7.58 (wide s, 1H, ═N—H); 7.42 (m, 1H,thiophene); 7.37 (m, 1H, thiophene); 7.01 (m, 1H, thiophene); 3.86 (s,3H, OCH₃).

[0921] IR: ν_(C═N) (carboximidate): 1630 cm⁻¹.

[0922] 27.5)(S)-N-{4-[4-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)-carbonyl]-1-piperazinyl]phenyl}-2-thiophenecarboximidamideDihydrochloride: 27

[0923] In a 150 ml erlen meyer flask, under a stream of argon, 8.2 g (20mmoles) of(S)-3,4-dihydro-2,5,7,8-tetramethyl-2-{4-[(4-aminophenyl)-1-piperazinyl]-carbonyl}-2H-1-benzopyran-6-ol(obtained as intermediate 13.2 but from (S)-Trolox®), is dissolved in 60ml of methanol and 4.2 g (30 mmoles) of methyl 2-thiophene carboximidateis added. The reaction medium is heated for 18 hours under reflux. Themethanol is evaporated under vacuum and the oily brown residue ispurified on a silica gel column (eluant: dichloromethane/ethanol: 95/5).The pure fractions are collected and concentrated under vacuum toproduce a brown oil with a yield of 68%. This oil is taken up in 22 mlof an ethanolic solution of HCl (1.3N) and diluted with 180 ml ofanhydrous acetone. The reaction medium is agitated for 1 hour at 0° C.The precipitate formed is filtered and washed successively with acetoneand ethyl ether. After drying, the dihydrochloride is obtained in theform of a pale yellow powder with a yield of 53%.

Example 283,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-{2-[3-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamideHydrochloride: 28

[0924] 28.1)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(3-nitrophenyl)ethyl]-benzamide:

[0925] The experimental protocol used is the same as that described forintermediate 5.1, with 3-nitrophenetylamine (J. Med. Chem. (1968), 11(1), 21-26) replacing the 4-nitrophenetylamine. A white powder isobtained with a yield of 50%. Melting point: 195-197° C.

[0926] NMR ¹H (100 MHz, CDCl₃, δ): 7.86 (m, 4H, Ph—NO₂); 7.50 (s, 2H,Ph); 6.10 (m, 1H, NHCO); 5.54 (s, 1H, OH); 3.75 (m, 2H, CH ₂—NHCO); 3.08(m, 2H, CH ₂—Ph—NO₂); 1.42 (s, 18H, 2×tBu).

[0927] 28.2)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(3-aminophenyl)ethyl]-benzamide:

[0928] The experimental protocol used is the same as that described forintermediate 5.2, with intermediate 28.1 replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-(4-nitrophenyl)ethyl]-benzamide.A white powder is obtained (yield of 40%) which is sufficiently pure tobe used directly in the following stage.

[0929] 28.3)3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[2-[3-[(2-thienyl(imino)methyl)amino]phenyl]ethyl}-benzamideHydrochloride: 28

[0930] The experimental protocol used is the same as that described forintermediate 1.3, with intermediate 28.2 replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Apale yellow powder is obtained with a yield of 35%. Melting point:205-207° C.

[0931] NMR ¹H (400 MHz, DMSO d6, δ): 11.59 (wide s, 1H, NH⁺); 9.89 (s,1H, NH⁺); 8.95 (s, 1H, NH⁺); 8.46 (s, 1H, CONH); 8.17 (m, 2H,thiophene); 7.54 (s, 2H, Ph—OH); 7.39 (m, 6H, thiophene, Ph—NH, OH);3.51 (m, 2H, CH ₂—NHCO); 2.89 (m, 2H, CH ₂—Ph—NH); 1.38 (s, 18H, 2×tBu).

[0932] IR: ν_(OH): 3624 cm^(−1,) ν_(C═O) (amide): 1631 cm^(−1,) ν_(C═N)(amidine): 1577 cm⁻¹.

Example 29N-{4-(4-[2-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-1-oxo-ethyl]-1-piperazinyl)phenyl}-2-thiophenecarboximidamideHydrochloride: 29

[0933] The experimental protocol used is the same as that described forthe compound 9, with 3,5-di-tert-butyl-4-hydroxyphenylacetic acidreplacing the 3,5-di-tert-butyl-4-hydroxybenzoic acid in the first stageof synthesis. Yellow powder. Melting point: 176-180° C.

[0934] NMR ¹H (400 MHz, DMSO d6, δ): 11.30 (wide s, 1H, NH⁺); 9.70 (wides, 1H, NH⁺); 8.65 (wide s, 1H, NH⁺); 8.10 (wide s, 2H, thiophene); 7.35(wide s, 1H, thiophene); 7.12 (m, 4H, Ph—N); 6.95 (s, 2H, Ph—OH); 6.80(wide s, 1H, OH); 3.60 (wide s, 6H, piperazine, CH₂CO); 3.10 (m, 4H,piperazine); 1.35 (s, 18H, 2×tBu).

[0935] IR: ν_(OH): 3620 cm^(−1,) ν_(C═O) (ester): 1638 cm^(−1;) ν_(C═N)(amidine): 1612 cm⁻¹.

Example 30 2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate Hydrochloride: 30

[0936] 30.1) 2-(4-nitrophenyl)ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxybenzoate:

[0937] In a 250 ml flask containing 80 ml of THF, under an argonatmosphere, 2.45 g (9.8 mmoles) of 3,5-di-tert-butyl-4-hydroxybenzoicacid, 1.8 g (10.8 mmoles) of 4-nitrobenzene-ethanol and 2.2 g (10.8mmoles) of dicyclohexylcarbodiimide are introduced successively, underagitation. The reaction medium is agitated for 15 hours at 20° C. andthe precipitate which appears is filtered out. The filtrate is washedwith 2×30 ml of a saturated NaCl solution, the organic phase is driedover magnesium sulphate, filtered and concentrated under vacuum. Theresidue is then crystallized using di-isopropyl ether. The solid isrecovered by filtration and 2.4 g (62%) of white crystals are obtainedafter drying. Melting point: 123.5-124.5° C.

[0938] NMR ¹H (100 MHz, CDCl₃, δ): 7.85 (m, 4H, Ph—NO,); 7.80 (s, 2H,Ph—OH); 5.70 (s, 1H, OH); 4.50 (m, 2H, O—CH₂); 3.20 (m, 2H, CH₂); 1.40(s, 18H, 2×tBu).

[0939] 30.2) 2-(4-aminophenyl)ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate:

[0940] The experimental protocol is the same as that described forintermediate 2.2, with intermediate 30.1 replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-[(4-nitrophenyl)-methyl]-benzamide.A white powder is obtained with a yield of 50%. Melting point: 135-136°C.

[0941] NMR ¹H (400 MHz, DMSO d6, δ): 7.75 (s, 2H, Ph—OH); 6.70 (m, 4H,Ph—N); 4.90 (wide s, 1H, OH); 4.25 (m, 2H, O—CH₂); 3.30 (wide s, 2H,NH₂); 2.80 (m, 2H, CH₂); 1.40 (s, 18H, 2×tBu).

[0942] 30.3) 2-{4-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate Hydrochloride: 30

[0943] The experimental protocol is the same as that described forintermediate 1.3, with intermediate 30.2 replacing the3,5-bis-(1,1-dimethylethyl)-4-hydroxy-N-(4-aminophenyl)-benzamide. Awhite solid is obtained with a yield of 26%. Melting point: 145-150° C.

[0944] NMR ¹H (400 MHz, DMSO d6, δ): 11.50 (wide s, 1H, NH⁺); 9.80 (wides, 1H, NH⁺); 8.90 (wide s, 1H, NH⁺); 8.20 (wide s, 2H, thiophene); 7.85(s, 1H, OH); 7.75 (s, 2H, Ph—OH); 7.47 (m, 5H, Ph—N, thiophene); 4.41(m, 2H, O—CH₂); 3.08 (m, 2H, CH₂); 1.40 (s, 18H, 2×tBu).

[0945] IR: ν_(C═O) (ester): 1700 cm^(−1,) ν_(C═N) (amidine): 1592 cm⁻¹.

Example 31 2-{3-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate Hydrochloride: 31

[0946] The experimental protocol used is the same as that described forthe compound 30, with 3-nitrobenzene-ethanol replacing the4-nitrobenzene-ethanol in the first stage of synthesis. Pale yellowpowder. Melting point: 145-148° C.

[0947] NMR ¹H (400 MHz, DMSO d6, δ): 11.50 (wide s, 1H, NH⁺); 9.82 (wides, 1H, NH⁺); 8.99 (wide s, 1H, NH⁺); 8.15 (m, 2H, thiophene); 7.81 (s,1H, OH); 7.75 (s, 2H, Ph—OH); 7.41 (m, 5H, Ph—N, thiophene); 4.41 (m,2H, O—CH₂); 3.08 (m, 2H, CH₂); 1.38 (s, 18H, 2×tBu).

[0948] IR: ν_(OH): 3620 cm^(−1,) ν_(C═O) (ester): 1707 cm^(−1,) ν_(C═N)(amidine): 1654 cm⁻¹.

Example 32 2-{2-[(2-thienyl(imino)methyl)amino]phenyl}ethyl3,5-bis-(1,1-dimethylethyl)-4-hydroxy-benzoate Hydrochloride: 32

[0949] The experimental protocol used is the same as that described forcompound 30, with 2-nitrobenzene-ethanol replacing the4-nitrobenzene-ethanol in the first stage of synthesis. Beige powder.Melting point: 139-145° C.

[0950] NMR ¹H (400 MHz, DMSO d6, δ): 11.50 (wide s, 1H, NH⁺); 9.80 (wides, 1H, NH⁺); 8.65 (wide s, 1H, NH⁺); 8.15 (m, 2H, thiophene); 7.80 (s,1H, OH); 7.70 (s, 2H, Ph—OH); 7.60 (m, 1H, Ph); 7.45 (m, 3H, Ph); 7.35(s, 1H, thiophene); 4.40 (m, 2H, O—CH₂); 3.00 (m, 2H, CH₂); 1.35 (s,18H, 2×tBu).

[0951] IR: ν_(C═O) (ester): 1728 cm^(−1,) ν_(C═N) (amidine): 1649 cm⁻¹.

Example 33 N-[4-(1H-imidazol-1-yl)phenyl]-2-thiophenecarboximidamideHydroiodide (33)

[0952] 33.1 1-(4-nitrophenyl)-1H-imidazole:

[0953] 9 g (64.5 mmoles) of potassium carbonate and 5 g (3.75 ml; 35.2mmol) of 1-fluoro-4-nitrobenzene are added to a solution of 2 g ofimidazole (29.4 mmol) in 14 ml of DMF. The reaction mixture is agitatedfor 1.5 hours at 110° C. Ethyl acetate (50 ml) is added to the mediumwhich is washed 3 times with 50 ml of water. The organic phases aredried over magnesium sulphate and concentrated under vacuum. 4.4 g ofproduct are thus obtained (yield=80%) in the form of a clear oil andused without further purification in the following stages.

[0954] NMR ¹H (CDCl₃, 100 MHz, δ): 6.92 (t, 1H, Arom. H imidazole), 7.16(s, 1H, Arom. H imidazole), 7.24-7.32-8.18-8.27 (4s, 4H, Arom. H), 7.59(s, 1H, Arom. H imidazole).

[0955] 33.2 1-(4-aminophenyl)-1H-imidazole:

[0956] 1-(4-nitrophenyl)-1H-imidazole (4.4 g; 23.5 mmoles) is put insolution in anhydrous methanol (140 ml) and palladium on carbon (0.44 g)is added to the medium. The reaction medium is placed under hydrogen for4 hours. The catalyst is filtered off and the solvent is evapored todryness. The expected product is obtained in a virtually pure state witha yield of 89% (3.3 g).

[0957] NMR ¹H (CDCl₃, 100 MHz, δ): 6.61-6.69-6.95-7.05 (4s, 4H, Arom.H), 6.88 (t, 1H, Arom. H imidazole), 7.07 (s, 1H, Arom. H imidazole),7.52 (s, 1H, Arom. H imidazole).

[0958] 33.3 N-[4-(1H-imidazol-1-yl)phenyl]-2-thiophenecarboximidamideHydroiodide (33):

[0959] 1-(4-aminophenyl)-1H-imidazole (0.3 g; 1.7 mmoles) andS-methyl-2-thiophenethiocarboximide hydroiodide (0.5 g; 1.75 mmoles) areput into solution in 1 ml isopropanol and 1 ml of DMF and the reactionmixture is agitated for 18 hours at 25° C. The precipitate formed isfiltered and washed with 15 ml of dichloromethane and 15 ml of ethanol.The expected product is thus obtained (0.48 g; 73%) in salified form(hydroiodide). Melting point: 252-253° C. (decomposition).

[0960] NMR ¹H (DMSO, 400 MHz, δ): 7.24 (s, 1H, arom. H). 7.38 (t, 1H,arom. H). 7.55-7.57-7.85-7.87 (4s, 4H, arom. H), 7.89 (s, 1H, arom. H),8.10 (m. 2H, arom. H), 8.50 (s, 1H, arom. H).

[0961] IR: ν_(C═N) (amidine): 1585 cm⁻¹.

Example 34N-[4-(3-thiazolidinylmethyl)phenyl]-2-thiophenecarboximidamide (34)

[0962] 34.1 1-bromomethyl-4-nitrobenzene:

[0963] 4-nitrobenzyl alcohol (6 g, 39 mmoles) is put into solution indichloromethane (100 ml) and carbon tetrabromide (14.9 g, 45 mmoles) isadded. Triphenylphosphine (11.8 g, 45 mmoles) is added in portions tothe medium at 0° C. Then the mixture is agitated for 2 hours at ambienttemperature. The solvent is evaporated off and the product obtained ispurified on silica gel in an ethyl acetate/heptane mixture (1/2). It isobtained in the form of white needle-shaped crystals (7.2 g; 85%).Melting point: 97-98° C.

[0964] NMR ¹H (CDCl₃, 100 MHz, δ): 4.53 (s, 2H, CH₂).7.53-7.61-8.18-8.27 (4 s, 4H, Arom. H).

[0965] 34.2 3-(4-nitrobenzyl)-thiazolidine:

[0966] A mixture of thiazolidine (0.9 g, 10 mmoles) and potassiumcarbonate (2.5 g, 18 mmoles) in acetonitrile (10 ml) is heated to 70° C.1-bromomethyl-4-nitrobenzene (2 g, 9.2 mmoles) in solution inacetonitrile (25 ml) is added dropwise and the reaction is maintainedunder reflux for 2 hours.

[0967] The precipitate formed is filtered, the mother liquors areevaporated and the residue is taken up in 50 ml of dichloromethane andwashed 3 times with 50 ml of water. The organic phases are dried,evaporated and purified over silica gel in an ethyl acetate/heptanemixture (1/2). The expected product is obtained in the form of acolourless oil (1.5 g, 72%).

[0968] NMR ¹H (CDCl₃, 100 MHz, δ): 3.05 (m, 4H, 2CH₂), 3.68 (s, 2H,CH₂—S), 4.04 (s, 2H, CH₂), 7.53-7.62-8.17-8.26 (4s, 4H, Arom. H).

[0969] 34.3 3-(4-aminobenzyl)-thiazolidine:

[0970] 3-(4-nitrobenzyl)-thiazolidine (1.1 g, 5 mmoles) is put intosolution in 10 ml concentrated hydrochloric acid at 0° C. Dihydrated tinchloride (7.7 g, 34 mmoles) is added in portions, the mixture is heatedfor 2 hours under reflux and the acid is evaporated off under reducedpressure. The residue is then taken up in 20 ml of water and neutralizedwith a 2N soda solution (approximately 100 ml). 100 ml ofdichloromethane is added to the medium and the whole is filtered oncelite in order to eliminate the salts in suspension. The organic phaseis extracted, washed 3 times with 50 ml of water, dried, filtered andevaporated to dryness under reduced pressure. The expected product ispurified on silica gel in a dichloromethane/methanol (98/2) mixture andis obtained in the form of of a beige powder (0.6 g, 63%). Meltingpoint: 73-74° C.

[0971] NMR ¹H (CDCl₃, 100 MHz, δ): 3.02 (m, 4H, 2CH₂). 3.44 (s, 2H,CH₂). 3.66 (wide s, 2H, NH₂), 4.07 (s, 2H, CH₂), 6.62-6.71-7.10-7.27 (4s, 4H, arom. H).

[0972] 34.4 [4-(3-thiazolidinylmethyl)phenyl]-2-thiophenecarboximidamide(34):

[0973] 3-(4-aminobenzyl)-thiazolidine (0.6 g, 3 mmoles) andS-methyl-2-thiophenethiocarboximide hydroiodide (1.14 g, 4 mmoles) areput into solution in 7 ml of an isopropanol/DMF mixture (2/5). Thereaction medium is agitated for 18 hours at ambient temperature. Then 10ml of ethyl acetate is added to the medium and the reaction product isextracted 3 times with 10 ml of water. The aqueous phase is collectedand basified with a saturated solution of sodium hydrogen carbonate,then the product is extracted 3 times with 10 ml of ethyl acetate. It ispurified on silica gel in a dichloromethane/methanol mixture (95/5) andis obtained in the form of a white powder (0.6 g, 65%). Melting point:161.5-163.5° C.

[0974] NMR ¹H (CDCl₃, 400 MHz, δ): 2.98 (t, 2H, CH₂), 3.14 (t, 2H, CH₂),3.54 (S, 2H, CH₂), 4.10 (s, 2H, CH₂), 4.85 (wide s, 2H, NH₂), 6.98 (s,1H, arom. H), 7.00 (s, 1H, arom. H), 7.10 (t, 1H, thiophene), 7.34 (s,1H, arom. H), 7.36 (s, 1H, arom. H), 7.42 (t, 1H, thiophene), 7.45 (m,1H, thiophene).

[0975] IR: ν_(C═N) (amidine): 1593 cm⁻¹.

Example 35N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamideFumarate (35)

[0976] 35.1 1-(4-nitrophenyl)-1,2,3,6-tetrahydropyridine:

[0977] The experimental protocol used is the same as that described forintermediate 33.1. 1,2,3,6-tetrahydropyridine replacing imidazole.Colourless oil.

[0978] NMR ¹H (CDCl₃, 100 MHz, δ): 2.33 (m, 2H, CH₂), 3.59 (t, 2H, CH₂),3.90 (m, 2H, CH₂), 5.90 (m, 2H, CH═CH), 6.75-6.82-8.07-8.18 (m, 4H,arom. H).

[0979] 35.2 1-(4-aminophenyl)-1,2,3,6-tetrahydropyridine:

[0980] The experimental protocol used is the same as that described forintermediate 34.3, 1-(4-nitrophenyl)-1,2,3,6-tetrahydropyridinereplacing 3-(4-nitrobenzyl)-thiazolidine. Colourless oil.

[0981] NMR ¹H (CDCl₃, 100 MHz, δ): 2.31 (m, 2H, CH₂), 3.21 (t, 2H, CH₂),3.43 (m, 2H, NH,), 3.56 (m, 2H, CH₂), 5.84 (m, 2H, CH═CH), 6.75 (m, 4H,arom. H).

[0982] 35.3N-[4-(1,2,3,6-tetrahydropyridin-1-yl)phenyl]-2-thiophenecarboximidamideFumarate (35):

[0983] The experimental protocol used is the same as that described forintermediate 33.3. 1-(4-aminophenyl)-1,2,3,6-tetrahydropyridinereplacing 1-(4-aminophenyl)-1H-imidazole. Beige powder. Melting point:193-194° C.

[0984] NMR ¹H (DMSO, 400 MHz, δ): 2.23 (m, 2H, CH₂), 3.29 (m, 2H, CH₂),3.61 (m, 2H, CH₂), 5.84 (m, 2H, CH═CH), 6.56 (s, 1H, fumaric acid), 6.89(m, 4H, arom. H), 7.13 (m, 1H, arom. H), 7.67 (m, 1H, arom. H), 7.77 (m,1H, arom. H).

[0985] IR: ν_(C═N) (amidine): 1560 cm⁻¹.

Example 36 N-[4-(1H-imidazol-1-ylmethyl)phenyl]-2-thiophenecarboximidamide Hydrochloride (36)

[0986] 36.1 1-(4-nitrobenzyl)-1H-imidazole:

[0987] The experimental protocol used is the same as that described forintermediate 33.1, 1-bromomethyl-4-nitrobenzene replacing1-fluoro-4-nitrobenzene. Colourless oil.

[0988] NMR ¹H (CDCl₃, 100 MHz, δ): 5.26 (s, 2H, CH₂), 6.92 (m, 1H, Himidazole), 7.16 (m, 1H, H imidazole), 7.59 (m, 1H, H imidazole),7.24-7.32-8.18-8.27 (4s, 4H, arom. H).

[0989] 36.2 1-(4-aminobenzyl)-1H-imidazole:

[0990] The experimental protocol used is the same as that described forintermediate 33.2, 1-(4-nitrobenzyl)-1H-imidazole replacing1-(4-aminophenyl)-1H-imidazole. Pale yellow powder. Melting point:121-122° C.

[0991] NMR ¹H (CDCl₃, 100 MHz, δ): 2.87 (wide s, 2H, NH₂), 4.98 (s, 2H,CH₂), 6.88 (m, 1H, H imidazole), 7.06 (m, 1H, H imidazole), 7.52 (m, 1H,H imidazole), 6.60-6.69-6.95-7.05 (4s, 4H, arom. H).

[0992] 36.3N-[4-(1H-imidazol-1-yl-ethyl)phenyl]-2-thiophenecarboximidamideHydrochloride (36):

[0993] The experimental protocol used is the same as that described forintermediate 34.4, 1-(4-aminobenzyl)-1H-imidazole replacing3-(4-aminobenzyl)-thiazolidine. After salification by a molar solutionof HCl in anhydrous diethyl ether, a beige powder is obtained. Meltingpoint: 261-263° C.

[0994] NMR ¹H (DMSO, 400 MHz, δ): 5.12 (s, 2H, CH₂), 6.46 (wide s, 2H,NH₂), 6.83-6.85-7.22-7.24 (4s, 4H, arom. H), 6.90 (s, 1H, arom. H), 7.09(t, 1H, arom. H), 7.20 (s, 1H, arom. H), 7.60 (d. 1H, arom. H), 7.74 (s,2H, arom. H).

[0995] IR: ν_(C═N) (amidine): 1599 cm⁻¹.

Example 37N-[4-{2-(3-thiazolidinyl)ethyl}phenyl]-2-thiophenecarboximidamide (37)

[0996] 37.1 4-(t-butoxycarbonylamino)-benzeneacetic Acid:

[0997] Para-aminophenylacetic acid (3 g, 20 mmoles) is dissolved in 60ml of a THF/H₂O mixture (2/1). 11 ml of 10% soda is added then 6 g ofdi-t-butyl-dicarbonate (28 mmol) in solution in 50 ml of a THF/H₂Omixture (2/1). Agitation is carried out for 18 hours at ambienttemperature. Then the THF is evaporated off under reduced pressure. Themedium is then acidified (pH=2) with a 10% solution of potassium acidsulphate (approximately 45 ml) and the reaction product is extractedwith 3 washings with ethyl acetate (3 times 50 ml). The organic phasesare dried and evaporated in order to produce 4.32 g (87%) of pure4-(t-butoxycarbonylamino)-benzeneacetic acid in the form of a beigepowder. Melting point: 149-150° C.

[0998] NMR ¹H (CDCl₃, 100 MHz, δ): 1.52 (s, 9H, tBu), 3.60 (s, 2H, CH₂),4.12 (wide s, 1H, COOH), 6.55 (s, 1H, NH), 7.21 (m, 4H, arom. H).

[0999] 37.2 (t-butoxycarbonylamino)-benzene Ethanol:

[1000] 4-(t-butoxycarbonylamino)-benzeneacetic acid (2.9 g, 11.4 mmoles)is dissolved in 10 ml of anhydrous THF at 0° C. and added to asuspension of LiAlH₄ (0.52 g, 13.6 mmoles) in 30 ml of THF. The reactionmixture is agitated at ambient temperature for 1.5 hours. 50 ml of ethylacetate then 20 ml of 2N soda are added to the medium. The expectedproduct is extracted from the organic phase, which is then washed with 3times 15 ml of water. The organic phase is dried and the solventevaporated off under reduced pressure. Then the reaction product ispurified on silica gel in a dichloromethane/methanol mixture (95/5). 1.1g (40%) is thus obtained in the form of a colourless oil.

[1001] NMR ¹H (CDCl₃, 100 MHz, δ): 1.53 (s, 9H, tBu), 2.82 (t, 2H, CH₂),3.83 (q, 2H, CH ₂—OH), 6.47 (s, TH, NH), 7.23 (m, 4H, arom. H).

[1002] 37.3 (2-bromoethyl-4-t-butoxycarbonylamino)benzene:

[1003] 4-(t-butoxycarbonylamino)-benzene ethanol (0.75 g, 3.1 mmoles)and carbon tetrabromide (1.2 g, 3.6 mmoles) are dissolved in 20 ml ofdichloromethane at 0° C. Triphenylphosphine (0.94 g, 3.6 mmoles) isadded in portions and the whole is agitated for 1 hour at ambienttemperature. The solvent is evaporated off under reduced pressure andthe product obtained is purified on silica gel in an ethylacetate/heptane mixture (1/2),1-(2-bromoethyl-4-t-butoxycarbonylamino)benzene is obtained in the formof a white powder (0.8 g, 84%). Melting point: 129-130° C.

[1004] NMR ¹H (CDCl₃, 100 MHz, δ): 1.52 (s, 9H, tBu), 3.11 (t, 2H, CH₂),3.54 (t, 2H, CH₂Br), 6.45 (s, 1H, NH), 7.22 (m, 4H, arom. H).

[1005] 37.4 3-12-[4-(t-butoxycarbonylamino)phenyl]ethyl}thiazolidine:

[1006] The experimental protocol used is the same as that described forintermediate 34.2, (2-bromoethyl-4-t-butoxycarbonylamino)benzenereplacing 1-bromomethyl-4-nitrobenzene. Colourless oil.

[1007] NMR ¹H (CDCl₃, 100 MHz, δ): 1.52 (s, 9H, tBu), 2.90 (m, 8H,4CH₂), 4.10 (s, 2H, N—CH₂—S), 6.46 (s, 1H, NH), 7.25 (m, 4H, arom. H).

[1008] 37.5 3-12-[4-aminophenyl]ethyl}thiazolidine:

[1009] 2.3 g (20 mmoles) of trifluoroacetic acid is added to a 100 mlflask containing a solution of 616 mg (2 mmoles) of intermediate 5.4 in10 ml of dichloromethane. After agitation for one hour at 20° C. thereaction mixture is concentrated to dryness under vacuum. The residue isdiluted with a mixture of 20 ml of dichloromethane and 20 ml of 4N soda.After decantation, the organic phase is washed successively with 3×20 mlof water followed by 20 ml of salt water. The organic solution is driedover sodium sulphate, filtered and the solvent is evaporated off underreduced pressure in order to obtain a colourless oil with a yield of72%.

[1010] NMR ¹H (CDCl₃, 100 MHz, δ): 2.85 (m, 8H, 4CH₂), 4.15 (s, 2H,N—CH₂—S), 7.25 (m, 4H, arom. H).

[1011] 37.6[4-[2-(3-thiazolidinyl)ethyl}phenyl]-2-thiophenecarboximidamide (37):

[1012] The experimental protocol used is the same as that described forintermediate 2.4, 3-{2-[4-aminophenyl]ethyl}thiazolidine replacing3-(4-aminobenzyl)-thiazolidine. Beige powder. Melting point: 60,5-61.5°C.

[1013] NMR ¹H (DMSO, 400 MHz, δ): 2.65 (t, 2H, CH₂), 2.82 (t, 2H, CH₂),2.91 (t, 2H, CH₂), 3.13 (t, 2H CH₂), 4.13 (s, 2H, N—CH₂—S),6.93-6.95-7.19-7.21 (4s, 4H, arom. H), 7.09 (t, 1H, H thiophene), 7.44(m, 2H, H thiophene).

[1014] IR: ν_(C═N) (amidine): 1591 cm⁻¹.

Example 38N-{4-[2-(1H-imidazol-1-yl)ethyl]phenyl}-2-thiophenecarboximidamideHydroiodide (38)

[1015] 38.1 1-2-[4-(t-butoxycarbonylamino)phenyl]ethyl]-1H-imidazole:

[1016] 2.5 g (18 mmoles) of K₂CO₃ is mixed together in a 100 ml flaskwith 680 mg (10 mmoles) of imidazole diluted in 10 ml of acetonitrile.The reaction mixture is heated at 70° C. before the dropwise addition ofa solution of 2 g (9.2 mmoles) of 1-bromomethyl-4-nitrobenzene insolution in 25 ml of acetonitrile. After agitation for 2 hours at thistemperature, the reaction mixture is cooled down and filtered in orderto eliminate the insoluble part. The filtrate is concentrated undervacuum and the residue is diluted in 50 ml of dichloromethane. Theorganic solution is successively washed with 3×50 ml of water and 50 mlof salt water. After drying over Na₂SO₄, filtration, the organic phaseis concentrated under vacuum and the residue purified on a silica column(eluant: dichloromethane/methanol: 95/5). Brown oil.

[1017] NMR ¹H (CDCl₃, 100 MHz, δ): 1.50 (s, 9H, tBu), 2.90 (t, 2H, CH₂),4.10 (t, 2H, CH₂), 6.50 (s, 1H, NH), 7.05 (m, 4H, arom. H), 6.85 (m, 1H,H imidazole), 7.03 (s, 1H, H imidazole), 7.32 (m, 1H, H imidazole).

[1018] 38.2 1-[2-(4-aminophenyl)ethyl]-1H-imidazole:

[1019] The experimental protocol used is the same as that described forintermediate 37.5,1-{2-[4-(t-butoxycarbonylamino)phenyl]ethyl}-1H-imidazole replacing3-{2-[4-(t-butoxycarbonyl amino)phenyl]ethyl}thiazolidine. Colourlessoil.

[1020] NMR ¹H (CDCl₃, 100 MHz, δ): 2.90 (t, 2H, CH₂), 3.35 (wide s, 2H,NH₂), 4.10 (t, 2H, CH₂), 6.70 (m, 4H, arom. H), 6.85 (m, 1H, Himidazole.), 7.03 (s, 1H, H imidazole.), 7.32 (m, 1H, H imidazole).

[1021] 38.3N-[4-[2-(1H-imidazol-1-yl)ethyl]phenyl]-2-thiophenecarboximidamideHydroiodide (38):

[1022] The experimental protocol used is the same as that described forintermediate 33.3, 1-[2-(4-aminophenyl)ethyl]-1H-imidazole replacing1-(4-aminophenyl)-1H-imidazole. Beige powder. Melting point: 214-215° C.

[1023] NMR ¹H (DMSO, 400 MHz, δ): 3.11 (t, 2H, CH₂), 4.33 (t, 2H, CH₂),7.29 (m, 6H. arom. H), 7.99 (m, 1H, arom. H), 8.70 (wide s, 2H, NH₂).

[1024] IR: ν_(C═N) (amidine): 1597 cm⁻¹.

Example 39N-{4-[2-(1,2,3,6-tetrahydropyridin-1-yl)ethyl]phenyl}-2-thiophenecarboximidamideFumarate (39)

[1025] 39.11-[2-[4-(t-butoxycarbonylamino)phenyl]ethyl]-1,2,3,6-tetrahydropyridine:

[1026] The experimental protocol used is the same as that described forintermediate 38.1, 1,2,3,6-tetrahydropyridine replacing thiazolidine.Colourless oil.

[1027] NMR ¹H (CDCl₃, 100 MHz, δ): 1.57 (s, 9H, tBu), 2.10 (m, 2H, CH₂),2.70 (m, 6H, 3CH₂), 3.00 (m, 2H, CH₂), 5.72 (m, 2H, CH═CH), 6.48 (s, 1H,NH), 7.10 (m, 4H, arom. H).

[1028] 39.2 1-[2-(4-aminophenyl)ethyl]-1,2,3,6-tetrahydropyridine:

[1029] The experimental protocol used is the same as that described forintermediate 37.5,1-{2-[4-(t-butoxycarbonylamino)phenyl]ethyl}-1,2,3,6-tetrahydropyridinereplacing 3-{2-[4-aminophenyl]ethyl}thiazolidine. Colourless oil.

[1030] NMR ¹H (CDCl₃, 100 MHz, δ): 3.20 (m, 2H, CH₂), 3.80 (m, 6H,3CH₂), 4.10 (m, 2H, CH₂), 4.57 (wide s, 2H, NH₂), 6.90 (m, 2H, CH═CH),8.00 (m, 4H, arom. H).

[1031] 39.3N-[4-[2-(1,2,3,6-tetrahydropyridin-1-yl)ethyl]phenyl]-2-thiophenecarboximidamideFumarate (39):

[1032] The experimental protocol used is same as that described forintermediate 33.3. 1-[2-(4-aminophenyl)ethyl]-1,2,3,6-tetrahydropyridinereplacing 1-(4-aminophenyl)-1H-imidazole. White powder. Melting point:128-129° C.

[1033] NMR ¹H (DMSO, 400 MHz, δ): 2.19 (m, 2H, CH₂), 2.83 (m, 6H, 3CH₂),3.25 (m, 2H, CH₂), 5.72 (m, 2H, CH═CH), 6.58 (s, 3H. fumaric acid),6.81-6.83-7.18-7.20 (4s, 4H, arom. H), 7.10 (t, 1H, H thiophene), 7.63(m, 1H, H thiophene), 7.75 (m, 1H, H thiophene).

[1034] IR: ν_(C═N) (amidine): 1620 cm⁻¹.

Example 40N-[4-(3-thiazolidinylcarbonylmethyl)phenyl]-2-thiophenecarboximidamide(40)

[1035] 40.13-[14-(t-butoxycarbonylamino)phenyl]methylcarbonyl]thiazolidine:

[1036] 4-(t-butoxycarbonylamino)-benzeneacetic acid (1.4 g, 5.6 mmoles).intermediate 37.1. and carbonyldiimidazole (0.9 g, 5.6 mmoles) aredissolved in 15 ml of THF. The reaction is maintained at ambienttemperature for 1 hour. Then thiazolidine (0.5 g, 5.6 mmol). in solutionin THF (5 ml), is added to the medium. The whole is agitated again for 2hours at ambient temperature. The solvents are evaporated off underreduced pressure. Then the residue is taken up in 25 ml ofdichloromethane and washed 3 times with 15 ml of water. The organicphase is dried and concentrated under reduced pressure.3-[{4-(t-butoxycarbonylamino)phenyl}methylcarbonyl]thiazolidine isobtained in the form of a white powder (1.43 g, 79%) and will be usedwithout further purification in the following stages. Melting point:223-224° C.

[1037] NMR ¹H (CDCl₃, 100 MHz, δ): 1.51 (s, 9H, tBu), 3.00 (m, 2H,CH₂—S), 3.67 (s, 2H, N—CH₂—S), 3.88 (m, 2H, CH₂—N), 4.52 (d, J=16 Hz,2H, CH₂—CO), 6.52 (wide s, 1H, NH), 7.26 (m, 4H, arom. H).

[1038] 40.2 3-[(4-aminophenyl)methylcarbonyl]thiazolidine:

[1039] 3-[(4-aminophenyl)methylcarbonyl]thiazolidine is obtained in theform of a colourless oil with a yield of 44% by following the operatingmethod described for intermediate 37.5.

[1040] NMR ¹H (CDCl₃, 100 MHz, δ): 1.62 (wide s, 2H, NH₂), 2.98 (m, 2H,CH₂—S), 3.61 (s, 2H, N—CH₂—S), 3.80 (m, 2H, CH₂—N), 4.52 (d. J=16 Hz.2H, CH₂—CO), 6.61-6.69-7.01-7.09 (4 s, 4H, arom. H).

[1041] 40.3[4-(3-thiazolidinylcarbonylmethyl)phenyl]-2-thiophenecarboximidamide(40):

[1042] The operating method used is the same as that described forintermediate 34.4, 3-[(4-aminophenyl)methylcarbonyl]thiazolidinereplacing 3-(4-aminobenzyl)thiazolidine. The free base is obtained witha yield of 64%. Melting point: 163.0-163.5° C.

[1043] NMR ¹H (CDCl₃, 400 MHz, δ): 3.01 (m, 2H, CH₂—S), 3.69 (d, J=6 Hz.2H, N—CH₂—S), 3.75-3.88 (2 t, 2H, CH₂—N), 4.55 (d, 2H, CH₂—CO), 4.87 (s,2H, NH₂), 6.95-6.97-7.22-7.24 (4 s, 4H, arom. H), 7.08 (t, 1H,thiophene), 7.43 (m, 2H, thiophene).

[1044] IR: ν_(C═O) (amide): 1630 cm⁻¹; ν_(C═N) (amidine): 1577 cm⁻¹.

Example 41N-(4-{[2-thiazolidinyl]carbonylaminomethyl}phenyl)-2-thiophenecarboximidamideFumarate (41)

[1045] 41.1 3-(t-butoxycarbonyl)thiazolidine-2-carboxylic Acid:

[1046] Thiazolidine-2-carboxylic acid (2 g, 15 mmoles) is agitated inthe presence of di-t-butyl dicarbonate according to the operating methoddescribed for intermediate 37.1.3-(t-butoxycarbonyl)thiazolidine-2-carboxylic acid is obtained in theform of a pale yellow oil with a yield of 97% (3.4 g) and will be usedas is in the following stages.

[1047] NMR ¹H (CDCl₃, 100 MHz, δ): 1.46 (s, 9H, tBu), 3.10 (m, 3H.CH₂—S, CH—S), 3.85 (m, 2H, CH₂—N).

[1048] 41.2(4-nitrobenzyl)-3-(t-butoxycarbonyl)thiazolidine-2-carboxamide:

[1049] 3-(t-butoxycarbonyl)thiazolidine-2-carboxylic acid (1 g, 4.3mmol) and carbonyldiimidazole (0.7 g, 4.3 mmol) are dissolved in THF (10ml). the mixture is agitated for 1 hour at ambient temperature.4-nitrobenzylamine (0.81 g, 4.3 mmoles) and triethylamine (0.6 ml. 0.43g, 4.3 mmoles) in suspension in 10 ml of a THF and DMF mixture (1/1) areadded to the preceding solution and the whole is heated under reflux for5 hours. The solvents are then evaporated off under reduced pressure.The residue is taken up in 25 ml of ethyl acetate and washed 3 timeswith 15 ml of water. The organic phase is dried and the solvent isevaporated off under reduced pressure. The product obtained is purifiedon silica gel in a dichloromethane/methanol mixture (95/5).N-(4-nitrobenzyl)-3-(t-butoxycarbonyl)thiazolidine-2-carboxamide isobtained in the form of a pale yellow oil with a yield of 80% (1.25 g).

[1050] NMR ¹H (CDCl₃, 100 MHz, δ): 1.45 (s, 9H, tBu), 3.09 (m, 3H,CH₂—S, CH—S), 3.86 (m, 2H, CH₂—CH ₂—N), 4.57 (m, 2H, CH₂—NH), 6.60 (wides, 1H, NH), 7.41-7.50-8.14-8.23 (4s, 4H, arom. H).

[1051] 41.3(4-aminobenzyl)-3-(t-butoxycarbonyl)thiazolidine-2-carboxamide:

[1052] A spatula tip's worth of Nickel of Raney is added to a solutionof 1.25 g (3.4 mmoles) ofN-(4-nitrobenzyl)-3-(t-butoxycarbonyl)thiazolidine-2-carboxamide in 2.5ml of methanol. The whole is taken to reflux and hydrazine hydrate (1.75ml) is added dropwise to the medium. The reaction is maintained for 1hour under reflux, then returned to ambient temperature. The catalyst isfiltered off and abundantly rinsed with methanol. The solvent isevaporated off under reduced pressure. Then the residue is taken up indichloromethane (20 ml) and washed 3 times with 15 ml of water. Theorganic phase is dried and the solvent is evaporated off under reducedpressure.N-(4-aminobenzyl)-3-(t-butoxycarbonyl)thiazolidine-2-carboxamide isobtained in the form of an inert yellow solid (0.815 g, 71%); it will beused in following stages without further purification.

[1053] NMR ¹H (CDCl₃, 100 MHz, δ): 1.43 (s, 9H, tBu), 3.08 (m, 2H,CH₂—S), 3.67 (m, 3H, CH₂—CH ₂—N, CH—S), 4.36 (m, 2H, CH₂—NH), 6.05 (wides, 1H, NH), 6.60-6.69-7.04-7.12 (4 s, 4H, arom. H).

[1054] 41.4[4-{[3-(t-butoxycarbonyl)-2-thiazolidinyl]carbonylaminomethyl}phenyl]-2-thiophenecarboximidamide:

[1055] The experimental protocol used is the same as that described forintermediate 34.4,N-(4-aminobenzyl)-3-(t-butoxycarbonyl)thiazolidine-2-carboxamidereplacing 3-(4-aminobenzyl)-thiazolidine. The expected compound isobtained with a yield of 77%.

[1056] NMR ¹H (CDCl₃, 100 MHz, δ): 1.45 (s, 9H, tBu), 3.14 (m, 3H,CH₂—S, CH—S), 3.84 (m, 2H, CH₂—CH ₂—N), 4.46 (m, 2H, CH₂—NH), 4.83 (wides, 2H, NH₂), 6.27 (wide s, 1H, NH), 7.22 (m, 7H, arom. H).

[1057] 41.5N-(4-{[2-thiazolidinyl]carbonylaminomethyl}phenyl)-2-thiophenecarboximidamideFumarate (41):

[1058] The experimental protocol used is the same as that described forintermediate 37.5.[4-{[3-(t-butoxycarbonyl)-2-thiazolidinyl]carbonylaminomethyl}phenyl]-2-thiophenecarboximidamidereplacing 3-{2-[4-aminophenyl]ethyl}thiazolidine. The expected compoundis obtained in the form of the free base with a yield of 34%. It issalified with an equivalent of fumaric acid in ethanol under reflux.Melting point: 167-168° C.

[1059] NMR ¹H (DMSO, 400 MHz, δ): 2.78 (t, 2H, CH₂—S), 3.06 (m, 2H,CH₂—CH ₂—N), 3.28 (wide s, 1H, CH—S), 4.26 (m, 2H, CH₂—NH), 4.86 (wides, 1H, NH), 6.45 (wide s, 2H, NH₂), 6.81-6.83-7.19-7.21 (4 s, 4H, arom.H), 7.10 (t, 1H, thiophene), 7.61 (d. 1H, thiophene), 7.74 (m, 1H,thiophene), 8.53 (t, 1H, NH—CO).

[1060] IR: ν_(C═O) (amide): 1624 cm^(−1;) ν_(C═N) (amidine): 1584 cm⁻¹.

Example 42N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-[4-{imino(2-thienyl)methylamino}phenyl]-2-furanCarboxamide Hydroiodide (42)

[1061] 42.1 2,6-di-t-butyl-4-nitrophenol:

[1062] 2,6-di-t-butylphenol (8 g, 39 mmoles) is dissolved in 25 ml ofcyclohexane at 10° C. A (1/1) mixture of nitric acid/acetic acid (5 ml)is added dropwise to the reaction medium maintained at this temperature.Agitation is then carried out for 15 minutes at ambient temperature.Then the precipitate formed is filtered off, rinsed with water andpentane. The 2,6-di-t-butyl-4-nitrophenol obtained (6.34 g, 65%) isdried in an oven and will be used without further purification in thefollowing stages. Pale yellow powder. Melting point: 167-168° C.

[1063] NMR ¹H (CDCl₃, 100 MHz, δ): 1.48 (s, 18H, 2tBu), 5.93 (s, 1H,OH), 8.13 (s, 2H, arom. H).

[1064] 42.2 2,6-di-t-butyl-4-aminophenol:

[1065] 2,6-di-t-butyl-4-nitrophenol (6.3 g, 25 mmoles) is dissolved inmethanol (100 ml), 0.6 g of palladium on carbon (10%) is added and thereaction medium is placed under a hydrogen atmosphere under 2 bars ofpressure. The catalyst is filtered out and the solvent is evaporated offunder reduced pressure. The residue is taken up in heptane and filtered.In this way 2,6-di-t-butyl-4-aminophenol (2.7 g, 48%) is obtained whichwill be used without further purification in the following stages. Pinkpowder. Melting point: 123-124° C.

[1066] NMR ¹H (CDCl₃, 100 MHz, δ): 6.60 (s, 2H, Ph); 4.65 (wide s, 1H,OH); 3.15 (wide s, 2H, NH₂); 1.42 (s, 18H, 2 tBu).

[1067] 42.3 N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-(4-nitrophenyl)-2-furanCarboxamide:

[1068] The experimental protocol used is the same as that described forintermediate 40.1, 2,6-di-t-butyl-4-aminophenol and5-(4-nitrophenyl)-2-furan carboxylic acid replacing thiazolidine and4-(t-butoxycarbonylamino)-benzeneacetic acid respectively. The expectedcompound is obtained in the form of a colourless oil with a yield of56%. RMN¹H (DMSO, 100 MHz, δ): 1.41 (s, 18H, 2tBu), 6.91 (s, 1H, OH),7.42 (m, 4H, arom. H), 7.54 (s, 2H, arom. H), 8.30 (m, 4H, arom. H),10.11 (s, 1H, NH).

[1069] 42.4 N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-(4-aminophenyl)-2-furanCarboxamide:

[1070] The experimental protocol used is the same as that described forintermediate 1.2.N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-(4-nitrophenyl)-2-furan carboxamidereplacing 1-(4-nitrophenyl)-1H-imidazole. The expected compound isobtained in the form of a colourless oil with a yield of 59%.

[1071] NMR ¹H (DMSO, 100 MHz, δ): 1.41 (s, 18H, 2 tBu), 4.70 (wide s,2H, NH₂), 6.91 (s, 1H, OH), 7.50 (m, 4H, arom. H), 7.54 (s, 2H, arom.H), 8.20 (m, 4H, arom. H).

[1072] 42.5N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-[4-{imino(2-thienyl)-methylamino}phenyl]-2-furanCarboxamide Hydroiodide (42):

[1073] The experimental protocol used is the same as that described forintermediate 33.3,N-(3,5-di-t-butyl-4-hydroxyphenyl)-5-(4-aminophenyl)-2-furan carboxamidereplacing 1-(4-aminophenyl)-1H-imidazole. The expected product isobtained in salified form with a yield of 27%. Melting point: 273-274°C.

[1074] NMR ¹H (DMSO, 400 MHz, δ): 1.40 (s, 18H, 2tBu), 6.90 (s, 1H, OH),7.45 (m, 5H, arom. H), 7.54 (s, 2H, arom. H), 8.15 (m, 4H, arom. H),9.05-9.90 (wide 2s's, 2H, NH₂), 10.01 (s, 1H, NH—CO), 11.57 (s, 1H, HI).

[1075] IR: ν_(OH): 3423-3242 cm⁻¹; ν_(C═O) (amide): 1646 cm⁻¹; ν_(C═N)(amidine): 1554 cm⁻¹.

Example 433-(3,5-di-t-butyl-4-hydroxyphenyl)-1-[4-{imino(2-thienyl)methylamino}phenyl]-2,5-imidazolidinedioneHydrochloride (43)

[1076] 43.1 Ethyl (3,5-di-t-butyl-4-hydroxyphenyl)amino Acetate:

[1077] 1 g (4.5 mmol) of 2,6-di-t-butyl-4-aminophenol (intermediate10.2) and 0.65 g of sodium acetate (7.9 mmol) are put into suspension in1 ml of ethanol. Then bromoethyl acetate (0.94 g, 5.65 mmol) is added tothe medium and the reaction medium is heated at 65° C. for 2 hours. Thereaction mixture is poured into 20 ml of ice-cooled water and thereaction product is extracted with dichloromethane (3 times 15 ml). Theorganic phases are dried and the solvent is evaporated off under reducedpressure. The residue is passed over silica gel in dichloromethane. Acolourless oil is obtained constituted by a mixture of 2 compounds: theproduct of mono- and di-substitution. The mixture of these 2 compoundsis used without further purification in the following stage.

[1078] 43.2 Ethyl(3,5-di-t-butyl-4-hydroxyphenyl)-(4-nitrophenylcarbamoyl)amino Acetate:

[1079] 1.13 g (4.2 mmoles) of intermediate 43.1 and 0.69 g (4.23 mmoles)of 4-nitrophenylisocyanate are dissolved in 9 ml of dichloromethane. Thereaction mixture is agitated for 2.5 hours at ambient temperature. Thesolvent is evaporated off under reduced pressure and the residue ispassed over silica gel in dichloromethane. In this way 0.66 g of pure(3,5-di-t-butyl-4-hydroxyphenyl)(4-nitrophenylcarbamoyl)aminoethylacetate is isolated in the form of a colourless oil. (Yield over 2stages: 31%).

[1080] NMR ¹H (CDCl₃, 100 MHz, δ): 1.30 (t, 3H, CH₃), 1.46 (s, 18H,2tBu), 4.23 (q, 2H, CH ₂—CH₃), 4.38 (s, 2H, CH₂—CO), 5.50 (s, 1H, OH),6.75 (wide s, 1H, NH), 7.28 (s, 2H, arom. H), 7.40-7.50-8.10-8.20 (4s,4H, arom. H).

[1081] 43.3(3,5-di-t-butyl-4-hydroxyphenyl)-1-(4-nitrophenyl)-2,5-imidazolidinedione:

[1082] 0.66 g (1.4 mmole) of intermediate 43.2 is dissolved in 10 ml ofethanol at 50° C. and the whole is heated at this temperature for 2hours. The precipitate formed is filtered off and washed with coldethanol. The compound obtained is used directly in the following stagewithout additional purification.

[1083] NMR ¹H (CDCl₃, 100 MHz, δ): 1.47 (s, 18H, 2tBu), 4.51 (s, 2H,N—CH₂—CO), 5.27 (s, 1H, OH), 7.33 (s, 2H, arom. H), 7.77-7.86-8.32-8.41(4s, 4H, arom. H).

[1084] 43.4(3,5-di-t-butyl-4-hydroxyphenyl)-1-(4-aminophenyl)-2,5-imidazolidinedione:

[1085] The experimental protocol used is the same as that described forintermediate 33.2,3-(3,5-di-t-butyl-4-hydroxyphenyl)-1-(4-nitrophenyl)-2,5-imidazolidinedionereplacing 1-(4-nitrophenyl)-1H-imidazole. The expected compound isobtained in the form of a white precipitate with a yield of 87%. It isused without additional purification in the following stage.

[1086] NMR ¹H (CDCl₃, 100 MHz): 1.47 (s, 18H, 2tBu), 4.45 (s, 2H,N—CH₂—CO), 5.18 (s, 1H, OH), 6.70-6.80-7.16-7.23 (4s, 4H, arom. H), 7.39(s, 2H, arom. H).

[1087] 43.53-(3,5-di-t-butyl-4-hydroxyphenyl)-1-[4-[imino(2-thienyl)-methylamino}phenyl]-2,5-imidazolidinedioneHydrochloride (43):

[1088] The experimental protocol used is the same as that described forintermediate 34.4,3-(3,5-di-t-butyl-4-hydroxyphenyl)-1-(4-aminophenyl)-2,5-imidazolidinedionereplacing 3-(4-aminobenzyl)-thiazolidine. The free base is salified bytreatment with a 1N solution of hydrochloric ether. The hydrochloride isobtained with a yield of 53%. Melting point: 258-265° C.

[1089] NMR ¹H (DMSO, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 4.65 (s, 2H,CH₂), 7.08 (s, 1H, OH), 7.40 (m, 3H, arom. H), 7.61 (s, 4H, arom. H),8.21 (m, 2H, arom. H), 9.20-9.95 (wide 2s's, 2H, NH₂), 11.75 (s, 1H,HCl).

[1090] IR: ν_(OH): 3637-3437 cm⁻¹; ν_(C═O) (imidazolidinedione): 1712cm⁻¹; ν_(C═O) (amidine): 1598 cm⁻¹.

Example 442-(3,5-di-t-butyl-4-hydroxyphenyl)-3-[4-{imino(2-thienyl)methylamino}phenyl]-4-thiazolidinoneHydrochloride (44)

[1091] 44.12-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-nitrophenyl)-4-thiazolidinone:

[1092] 5 g of 3,5-di-t-butyl-4-hydroxybenzaldehyde (21 mmol) and 2.95 gof para-nitroaniline (21 mmol) are dissolved in 50 ml of anhydroustoluene. 0.5 ml of glacial acetic acid is added and the whole is takento reflux for 24 hours. Then 1.96 g of mercaptoacetic acid (21 mmol) isadded to the medium and reflux is continued for another 24 hours. Afterthe reaction mixture has returned to ambient temperature, it is washedwith water (3 times 30 ml). After decantation. the organic phase isdried over sodium sulphate and the solvent is evaporated off underreduced pressure. The residue is purified on silica gel in an ethylacetate/heptane mixture (1/4) and 1.33 g of pure2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-nitrophenyl)-4-thiazolidinone isobtained in the form of a colourless oil (15%).

[1093] NMR ¹H (CDCl₃, 100 MHz, δ): 1.36 (s, 18H, 2tBu), 3.91 (s, 2H,CH—S), 5.28 (s, 1H, CH—S), 6.20 (s, 1H, OH), 7.03 (s, 2H, arom. H),7.38-7.48-8.11-8.20 (4 s, 4H, arom. H).

[1094] 44.22-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-aminophenyl)-4-thiazolidinone:

[1095] 1.3 g of2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-nitrophenyl)-4-thiazolidinone (3mmol) and 3.4 g (15 mmol) of dihydrated tin chloride are dissolved in 25ml of ethyl acetate. The reaction is maintained for 2 hours at 70° C.After the mixture has returned to ambient temperature, it is poured intoa saturated solution of sodium hydrogen carbonate. The expected productis then extracted from the organic phase then it is washed 3 times with10 ml of water. The2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-aminophenyl)-4-thiazolidinone ispurified on silica gel in an ethyl acetate/heptane mixture (1/1) and isobtained in the form of a beige oil with a yield of 69% (0.82 g).

[1096] NMR ¹H (CDCl₃, 100 MHz, δ): 1.37 (s, 18H, 2tBu), 3.64 (wide s,2H, NH₂), 3.89 (s, 2H, CH₂—S), 5.22 (s, 1H, CH—S), 5.91 (s, 1H, OH),6.51-6.59-6.78-6.86 (4 s, 4H, arom. H), 7.04 (s, 2H, arom. H).

[1097] 44.32-(3,5-di-t-butyl-4-hydroxyphenyl)-3-[4-{imino(2-thienyl)-methylamino}phenyl]-4-thiazolidinoneHydrochloride (44):

[1098] The experimental protocol used is the same as that described forintermediate 34.4,2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-aminophenyl)-4-thiazolidinonereplacing 3-(4-aminobenzyl)-thiazolidine. The expected compound isobtained in salified form (hydrochloride) by treatment of the free basewith a 1N solution of hydrochloric ether with a yield of 43%. Meltingpoint: 58-61° C.

[1099] NMR ¹H (DMSO, 400 MHz, δ): 1.32 (s, 18H, 2tBu), 3.93 (m, 2H,CH—S), 6.57 (s, 1H, CH—S), 7.08 (s, 2H, arom. H), 7.41 (m, 5H, arom. H),8.15 (m, 2H, arom. H), 9.10-9.90 (wide 2s's, 2H, NH₂), 11.45 (wide s,1H, HCl).

[1100] IR: ν_(OH): 3624-3423 cm⁻¹; ν_(C═O) (thiazolidinone): 1679-1658cm⁻¹; ν_(C═N) (amidine): 1568 cm⁻¹.

Example 455-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-[4-{imino(2-thienyl)methylamino}phenyl]-2,4-imidazolidinedioneFumarate (45)

[1101] 45.1]-Methyl-3-(4-nitrophenyl)-2,4-imidazolidinedione:

[1102] 0.47 g of the ethyl ester of sarcosine, HCl (3 mmoles) isdissolved in 5 ml of dichloromethane and 0.42 ml (3 mmoles) oftriethylamine is added. 0.5 g of 4-nitrophenylisocyanate (3 mmoles) insolution in 5 ml of dichloromethane is added dropwise in the precedingmixture and the reaction mixture is maintained for 30 minutes at ambienttemperature. The organic solution is then washed with water (3 times 10ml) then dried and the solvent is evaporated off under reduced pressure.The residue is taken up in 10 ml of ethanol and the reaction medium isheated under reflux for 2 hours, After the reaction medium has returnedto ambient temperature, the precipitate formed is filtered. In this way1-methyl-3-(4-nitrophenyl)-2,4-imidazolidinedione is obtained with ayield of 72% (0.5 g) and will be used without further purification inthe following stage.

[1103] NMR ¹H (CDCl₃, 100 MHz, δ): 3.11 (s, 3H, CH₃), 4.09 (s, 2H, CH₂),7.70-7.79-8.27-8.37 (4 s, 4H, arom. H).

[1104] 45.25-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-(4-nitrophenyl)-2,4-imidazolidinedione:

[1105] Intermediate 45.1 (0.5 g, 2.13 mmol),3,5-di-t-butyl-4-hydroxybenzaldehyde (0.5 g, 2.13 mmol) and β-alanine(0.123 g, 1.4 mmol) are dissolved in acetic acid (10 ml). The reactionis maintained under reflux for 24 hours. After the reaction medium hasreturned to ambient temperature, 40 ml of water is added to the mediumand the whole is agitated for 1 hour. The precipitate formed is filteredand washed with water. The filtrate is concentrated under vacuum and theevaporation residue is purified on silica gel (eluant: heptane/ethylacetate: 4/1). The pure fractions are collected and concentrated todryness in order to produce the expected product with a yield of 32%(0.3 g).

[1106] NMR ¹H (CDCl₃, 100 MHz, δ): 1.49 (s, 18H, 2tBu), 3.35 (s, 3H,CH₃), 5.59 (s, 1H, OH), 6.40 (s, 1H, CH═C), 7.75-7.84-8.31-8.40 (4 s,4H, arom. H), 7.92 (s, 2H, arom. H).

[1107] 45.35-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-(4-aminophenyl)-2,4-imidazolidinedione:

[1108] The experimental protocol used is the same as that described forintermediate 44.2,5-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-(4-nitrophenyl)-2,4-imidazolidinedionereplacing2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-nitrophenyl)-4-thiazolidinone.The expected compound is obtained with a yield of 45%.

[1109] NMR ¹H (CDCl₃, 100 MHz, δ): 1.47 (s, 18H, 2tBu), 3.30 (s, 3H,CH₃), 5.51 (s, 1H, OH), 6.28 (s, 1H, CH═C), 6.69-6.78-7.12-7.21 (4 s,4H, arom. H), 7.91 (s, 2H, arom. H).

[1110] 45.45-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-[4-{imino(2-thienyl)methylamino}phenyl]-2,4-imidazolidinedioneFumarate (45):

[1111] The experimental protocol used is the same as that described forintermediate 34.4,5-[(3,5-di-t-butyl-4-hydroxyphenyl)methylene]-1-methyl-3-(4-aminophenyl)-2,4-imidazolidinedionereplacing 3-(4-aminobenzyl)-thiazolidine. The expected compound isobtained in salified form (fumarate) by treatment of the free base withan equivalent of fumaric acid in ethanol while warm with a yield of 35%.Melting point: 54,5-57.5° C.

[1112] NMR ¹H (DMSO, 400 MHz, δ): 1.40 (s, 18H, 2tBu), 3.22 (s, 3H,CH₃), 6.59 (s, 1H, CH═C), 6.61 (s, fumaric acid), 6.97-6.99-7.30-7.32 (4s, 4H, arom. H), 7.11 (t, 1H, thiophene), 7.64 (d, 1H, thiophene), 7.79(m, 1H, thiophene), 7.96 (s, 2H, arom. H).

[1113] IR: ν_(OH): 3618-3433 cm⁻¹; ν_(C═O) (imidazolidinedione): 1711cm⁻¹; ν_(C═N) (amidine): 1585 cm⁻¹.

Example 462-(S)-4-(S)-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)-phenyl]-4-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-prolinamideHydrochloride (46)

[1114] 46.1 Methyl ester of2-(S)-4-(S)-1-[(1,1-dimethylethoxy)carbonyl]-4-(4-nitrophenoxy)-proline:

[1115] A solution of 4.37 g (30.7 mmoles) of 4-nitrophenol in 30 ml ofanhydrous N-methyl-2-pyrrolidinone is added slowly to a suspension.cooled down to 0° C., of 1.23 g (30.7 mmol) of NaH at 60% in suspensionin 30 ml of anhydrous N-methyl-2-pyrrolidinone, under an inertatmosphere. After agitation for one hour at 0° C., the prolinederivative (6 g, 15 mmol) is added in one go. The reaction mixture isagitated at 20° C. for 15 hours followed by heating at 80° C. for 2hours in order to complete the reaction. After the reaction mixture hasreturned to 20° C., 200 ml of ethyl acetate and 100 ml of 1N soda areadded to the medium. After decantation, the organic phase is washedsuccessively with dilute solutions of 1N soda until complete extractionof the unreacted phenolic derivative, 2×100 ml of water and 100 ml ofsalt water. The organic solution is dried over sodium sulphate, filteredand concentrated to dryness under reduced pressure, in order to producea light yellow oil which crystallizes spontaneously in air. The crystalsare collected and washed with 3×50 ml of ethyl ether. After drying,colourless crystals are obtained with a yield of 63%. Melting point:155-157° C.

[1116] NMR ¹H (DMSO, 400 MHz, δ): 1.34-1.40 (2s, 9H, tBu); 2.45 (m, 2H,CH₂); 3.60 (m, 2H, CH₂—N); 3.58-3.63 (2s, 3H, O—CH₃); 4.40 (m, 1H,CH—CO₂); 5.22 (m, 1H, HC—O); 7.63 (m, 4H, Ph).

[1117] 46.22-(S)-4-(S)-1-[(1,1-dimethylethoxy)carbonyl]-4-(4-nitrophenoxy)-proline:

[1118] 730 mg (approximately 16 mmol) of potash diluted in 5 ml of wateris added at 20° C. to a 100 ml flask containing 2.87 g (7.84 mmol) ofcompound 46.1 in 40 ml of ethanol. After agitation for 15 hours, thereaction mixture is diluted with 100 ml of ethyl acetate. acidified at0° C. with a 12N solution of HCl and decanted. The organic phase iswashed with 50 ml of water followed by 50 ml of salt water. After dryingover sodium sulphate, the organic solution is filtered and concentratedto dryness under vacuum. 2.67 g of a white powder is obtained which isused directly in the following stage without additional purification.

[1119] NMR ¹H (CDCl₃, 100 MHz, δ): 1.50 (s, 9H, tBu); 2.60 (m, 2H, CH₂);3.80 (m, 2H, CH₂—N); 4.60 (m, 1H, CH—CO₂); 5.07 (m, 1H, HC—O); 7.58 (m,4H, Ph); 8.95 (wide s, 1H, CO₂H).

[1120] 46.32-(S)-4-(S)-1-[(1,1-dimethylethoxy)carbonyl]-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-4-(4-nitrophenoxy)-prolinamide:

[1121] 1.28 g (6.20 mmol) of dicyclohexylcarbodiimide is added at 0° C.to a solution of 1.99 g (5.64 mmol) of intermediate 46.2, 1.25 g (5.64mmol) of intermediate 42.2 and 845 mg (6.20 mmol) ofhydroxybenzotriazole in 25 ml of DMF. After agitation for 24 hours at20° C., the reaction mixture is filtered and the precipitate is washedwith ethyl acetate. The filtrate is diluted with 100 ml of ethyl acetateand washed successively with 2×40 ml of 1N soda, 2×40 ml of water and 40ml of salt water. After drying over sodium sulphate, the organicsolution is filtered and concentrated to dryness under vacuum in orderto produce a brown oil which is purified on a silica column (eluantheptane/ethyl acetate: 1/1). The pure fractions are collected and afterconcentration under vacuum, 1.35 g (43%) of a beige powder is obtained.Melting point: 117-120° C.

[1122] NMR ¹H (CDCl₃, 100 MHz, δ): 1.20-1.70 (m, 27H. 3×tBu); 2.68 (m,2H, CH₂); 3.80 (m, 2H, CH₂—N); 4.58 (m, 1H, CH—CO₂); 5.10 (m, 2H, OH,HC—O); 7.25-7.28 (2s, 2H, Ph—OH); 7.51 (m, 4H, Ph—NO₂); 8.00 (wide s,1H, NHCO).

[1123] 46.42-(S)-4-(S)-1-[(1,1-dimethylethoxy)carbonyl]-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-4-(4-aminophenoxy)-prolinamide.

[1124] 1.35 g (2.4 mmol) of intermediate 46.3 in 30 ml of ethanol isdissolved in an autoclave equipped with a magnetic stirrer in thepresence of ½ a spatula's worth of Pd/C at 10%. The reaction mixture isagitated under 1.5 bar of hydrogen for 3 hours. After filtration oncelite, the filtrate is concentrated under vacuum. The residue is takenup in a 1/1 ethyl ether/heptane mixture and after crystallization, it isfiltered and rinsed using heptane. A beige powder is obtained with ayield of 60%. Melting point: 112-113° C.

[1125] NMR ¹H (CDCl₃, 100 MHz, δ): 1.20-1.70 (m, 27H, 3×tBu); 2.55 (m,2H, CH₂); 3.50 (wide s, 2H, NH₂); 3.75 (m, 2H, CH₂—N); 4.48 (m, 1H,CH—CO₂); 4.80 (m, 1H, HC—O); 5.10 (s, 1H, OH); 6.65 (m, 4H, Ph—NH₂);7.28 (m, 2H, Ph—OH); 8.00 (wide s, 1H, NHCO).

[1126] 46.52-(S)-4-(S)-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-4-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-prolinamideHydrochloride (46):

[1127] A mixture of 694 mg (1.32 mmol) of intermediate 46.4 is heated at50° C. for 48 hours in the presence of 376 mg (1.32 mmol) ofS-methyl-2-thiophenethiocarboximide hydroiodide in solution in 15 ml ofisopropanol. The reaction mixture is then concentrated to dryness undervacuum and the evaporation residue is suspended in 50 ml of ethylacetate. After the addition of 50 ml of a saturated solution of Na₂CO₃the organic phase is decanted and successively washed with 25 ml of asaturated solution of Na₂CO₃, 50 ml of water and 50 ml of salt water.After drying over sodium sulphate, the organic solution is filtered andconcentrated to dryness under vacuum in order to produce a yellow powderwhich is purified on a silica column (eluant: ethyl acetate). The purefractions are collected and after concentration under vacuum. 686 mg(82%) of a beige powder is obtained which is immediately dissolved in 5ml of a 4M solution of HCl in 1,4-dioxan. After agitation for 15 hoursat 20° C., 20 ml of dry ethyl ether is added to the reaction mixture.The precipitate which appears is then filtered off, rinsed with 2×25 mlof dry ethyl ether and dried in an oven in order to produce 270 mg of abeige powder. Melting point: 233,5-235° C.

[1128] NMR ¹H (DMSO, 400 MHz, δ): 1.37 (s, 18H, 2×tBu); 2.61 (m, 2H,CH₂); 3.60 (m, 2H, CH₂—N); 4.56 (m, 1H, CH—CO₂); 5.25 (m, 1H, HC—O);6.92 (s, 1H, OH); 7.21 (m, 4H, Ph—N); 7.38 (m, 1H, thiophene); 7.45 (s,2H, Ph—OH); 8.18 (m, 2H, thiophene); 8.78 (wide s, 1H, NH⁺); 9.09 (wides, 1H, NH⁺); 9.80 (wide s, 1H, NH⁺); 10.68 (c. 1H, CONH); 11.42 (wide s,1H, NH⁺).

[1129] IR: ν_(OH): 3624-3420 cm⁻¹; ν_(C═O) (amide): 1653 cm⁻¹; n_(C═N)(amidine): 1610 cm⁻¹.

Example 475,6-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1-(2H)pyridineCarboxamide Hydrochloride (47)

[1130] 47.1 5,6-dihydro-N-(4-nitrophenyl)-1-(2H)-pyridine Carboxamide:

[1131] 900 mg (5 mmol) of 4-nitrophenylisocyanate is dissolved, under anargon atmosphere, in a 100 ml three-necked flask in 17 ml of dry DMF.0.45 ml (5 mmol) of 1,2,3,6-tetrahydropyridine is added to this solutionin one go, and agitation is maintained for 15 hours. The reactionmixture is then concentrated to dryness under vacuum and the evaporationresidue placed on a silica gel column. After elution with aheptane/ethyl acetate mixture: 4/6, the pure fractions are collected andconcentrated under reduced pressure in order to produce 860 mg (70%) ofa bright yellow powder. Melting point: 169-170° C.

[1132] NMR ¹H (DMSO, 100 MHz, δ): 2.29 (m, 2H, ═CH—CH₂); 3.69 (m, 2H,CH₂—N); 4.10 (m, 2H, ═CH—CH₂—N); 5.91 (m, 2H, CH═CH); 8.09 (m, 4H, Ph);9.32 (wide s, 1H, NHCO).

[1133] 47.2 N-(4-aminophenyl)-5,6-dihydro-1-(2H)-pyridine Carboxamide:

[1134] The experimental protocol used is the same as that described forintermediate 44.2, 5,6-dihydro-N-(4-nitrophenyl)-1-(2H)-pyridinecarboxamide replacing2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-nitrophenyl)-4-thiazolidinone. Abrown oil is obtained with a yield of 36%.

[1135] NMR ¹H (CDCl₃+D₂O, 400 MHz, δ): 2.20 (m, 2H, ═CH—CH₂); 3.59 (m,2H, CH₂—N); 3.95 (m, 2H, ═CH—CH₂—N); 5.84 (m, 2H, CH═CH); 6.90 (m, 4H,Ph); 9.32 (wide s, 1H, NHCO).

[1136] 47.35,6-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1-(2H)-pyridineCarboxamide Hydrochloride (47):

[1137] The experimental protocol used is the same as that described forintermediate 46.5, N-(4-aminophenyl)-5,6-dihydro-1-(2H)-pyridinecarboxamide replacing2-(S)-4-(S)-1-[(1,1-dimethylethoxy)carbonyl]-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-4-(4-aminophenoxy)-prolinamide.After salification, using a solution of 1M HCl in ethyl ether, a paleyellow powder is obtained with a yield of 55%. Melting point: 230-231°C.

[1138] NMR ¹H (DMSO, 400 MHz, δ): 2.16 (m, 2H, ═CH—CH₂); 3.59 (m, 2H,CH₂—N); 3.98 (m, 2H, ═CH—CH₂—N); 5.80 (m, 2H, CH═CH); 7.52 (m, 4H, Ph);7.38 (s, 1H, thiophene); 8.16 (m, 2H, thiophene); 8.78 (wide s, 1H,NH⁺); 8.81 (s, 1H, CONH); 9.73 (wide s, 1H, NH⁺); 11.41 (wide s, 1H,NH⁺).

[1139] IR: ν_(C═O) (urea): 1637 cm⁻¹; ν_(C═N) (amidine): 1583 cm⁻¹.

Example 48N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(R.S)-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-(R)-thiazolidineCarboxamide Fumarate (48)

[1140] 48.1 2-(R.S)-(4-nitrophenyl)-4-(R)-thiazolidine carboxylic Acid:

[1141] 3 g (17.08 mmoles) of L-Cysteine hydrochloride and 2.18 g (22.2mmoles) of sodium acetate are dissolved in 75 ml of water. The solutionis agitated vigorously during the addition. by portions, of 3.10 g (20.5mmoles) of 4-nitrobenzaldehyde in solution in 80 ml of 95% ethanol. Awhite precipitate rapidly appears in this pale yellow solution whichforms abundantly. Agitation is maintained for one hour, the reactionmixture is then cooled down to 0° C. and filtered. The precipitate issuccessively rinsed with 200 ml of water, 100 ml of cold ethanol and 100ml of ethyl ether. After drying. a white powder is obtained with a yieldof 87%. Melting point: 120-121° C.

[1142] NMR ¹H (Acetone D6, 100 MHz, δ): 3.50 (m, 2H, CH₂—S); 4.25 (m,1H, CH—CO); 4.75 (hump, 2H, CO₂H+NH); 5.86 (s, 1H, N—CH—S); 8.20 (m, 4H,Ph).

[1143] 48.23-[(1,1-dimethylethoxy)carbonyl]-2-(R,S)-(4-nitrophenyl)-4-(R)-thiazolidineCarboxylic Acid:

[1144] The experimental protocol used is the same as that described forintermediate 47.1, 2-(R,S)-(4-nitrophenyl)-4-(R)-thiazolidine carboxylicacid replacing 4-(t-butoxycarbonylamino)-benzeneacetic acid. A paleyellow powder is obtained with a yield of 59%. Melting point: 145-146°C.

[1145] NMR ¹H (CDCl₃, 100 MHz, δ): 1.35 (m, 9H, tBu); 3.40 (m, 2H,CH₂—S); 4.95 (m, 1H, CH—CO); 6.10 (m, 1H, N—CH—S); 8.00 (m, 4H, Ph);10.00 (wide s, 1H, CO₂H).

[1146] 48.33-[(1,1-dimethylethoxy)carbonyl]-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(R,S)-(4-nitrophenyl)-4-(R)-thiazolidine Carboxamide:

[1147] The experimental protocol used is the same as that described forintermediate 46.3,3-[(1,1-dimethylethoxy)carbonyl]-2-(R,S)-(4-nitrophenyl)-4-(R)-thiazolidinecarboxylic acid replacing2-(S)-4-(S)-1-[(1,1-dimethylethoxy)carbonyl]-4-(4-nitrophenoxy)-proline.A white powder is obtained with a yield of 41%. Melting point: 226-227°C.

[1148] NMR ¹H (CDCl₃, 100 MHz, δ): 1.45 (m, 27H, 3×tBu); 3.52 (m, 2H,CH₂—S); 5.00 (m, 1H, CH—CO); 5.15 (s, 1H, OH); 6.10 (wide s, 1H,N—CH—S); 7.30 (s, 2H, Ph—OH); 7.92 (m, 4H, Ph—NO₂); 8.60 (wide s, 1H,CONH).

[1149] 48.43-[(1,1-dimethylethoxy)carbonyl]-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(R,S)-(4-aminophenyl)-4-(R)-thiazolidineCarboxamide:

[1150] The experimental protocol used is the same as that described forintermediate 44.2,3-[(1,1-dimethylethoxy)carbonyl]-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(R,S)-(4-nitrophenyl)-4-(R)-thiazolidinecarboxamide replacing2-(3,5-di-t-butyl-4-hydroxyphenyl)-3-(4-nitrophenyl)-4-thiazolidinone.The expected product is obtained in the form of a pale yellow powderwith a yield of 21%. Melting point: 196-198° C.

[1151] NMR ¹H (CDCl₃, 100 MHz, δ): 1.40 (m, 27H, 3×tBu); 3.50 (m, 4H,CH₂—S+NH₂); 5.00 (m, 1H, CH—CO); 5.10 (s, 1H, OH); 6.01 (wide s, 1H,N—CH—S); 6.98 (m, 4H, Ph—NH₂); 7.25 (s, 2H, Ph—OH); 8.50 (wide s, 1H,CONH).

[1152] 48.5 N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-2-(R,S)-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-(R)-thiazolidineCarboxamide Fumarate (48):

[1153] The experimental protocol used is the same as that described forintermediate 46.5, intermediate 48.4 replacing2-(S)-4-(S)-1-[(1,1-dimethylethoxy)carbonyl]-N-[4-hydroxy-3,5-bis-(1,1-dimethylethyl)phenyl]-4-(4-aminophenoxy)-prolinamide.Compound 48.5 obtained in the form of the free base is then salified inthe presence of fumaric acid under reflux of ethanol for 30 minutes. Ayellow powder is obtained with an overall yield of 30%. Melting point:201-204° C.

[1154] NMR ¹H (DMSO, 400 MHz, δ): 1.37 (s, 18H, 2×tBu); 3.17 (m, 2H,CH₂—S); 3.29 (wide s, 1H, NH thiazolidine); 3.91 (m, H, CH—CO); 4.31 (m,_H, CH—CO); 5.59 (s, _H, N—CH—S); 5.67 (s, _H, N—CH—S); 6.61 (s, 2H,fum,); 6.74 (m, 2H, NH₂ amidine); 7.11 (m, 1H, thiophene); 7.19 (m, 4H,Ph—N); 7.42 (s, 2H, Ph—OH); 7.62 (m, 1H, thiophene); 7.73 (wide s, 1H,thiophene); 9.69 (s, _H, CONH); 9.95 (s, _H, CONH).

[1155] IR: ν_(OH): 3625-3421 cm⁻¹; ν_(C═O) (amide): 1652 cm⁻¹; ν_(C═N)(amidine): 1604 cm⁻¹.

Example 49N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-thiazolecarboxamideHydroiodide (49)

[1156] 49.1 4-nitrobenzene-carbothioamide:

[1157] 6.06 g (15 mmol) of Lawesson reagent is added to a solution of4.15 g (25 mmol) of 4-nitrobenzamide in 100 ml of 1,4-dioxan. Thereaction mixture is heated under reflux for two hours. After thesolution has returned to ambient temperature, it is poured into 150 mlof water and extracted with 5 times 100 ml of ethyl acetate. The organicsolution is dried over magnesium sulphate, filtered and concentratedunder vacuum in order to produce a yellow oil which is purified on asilica gel column (eluant: heptane/ethyl acetate 1/1). The purefractions are collected and concentrated under vacuum. 3.26 g of ayellow powder is obtained with a yield of 72%. Melting point: 165-167°C.

[1158] 49.2 Ethyl 2-(4-nitrophenyl)-4-thiazolecarboxylate:

[1159] 3.26 g (17.9 mmol) of intermediate 49.1 and 2.26 ml (18 mmol) ofethyl bromopyruvate are introduced successively into a flask containing100 ml of DMF. After agitating the reaction mixture at 23° C., for 1hour, the solution is concentrated under vacuum. The evaporation residueis dissolved in 150 ml of dichloromethane and washed successively with100 ml of water and 100 ml of salt water. After drying over magnesiumsulphate and filtration, the organic solution is concentrated undervacuum. The powder obtained is then agitated in the presence of 100 mlof a (3/1) mixture of toluene and ethanol, filtered and rinsed with 25ml of the same mixture of solvents. 3.2 g (60%) of a beige powder isobtained. Melting point: 156-158° C.

[1160] 49.3 2-(4-nitrophenyl)-4-thiazolecarboxylic Acid:

[1161] A solution of 0.82 g (14.5 mmol) of KOH in 5 ml of water is addeddropwise at 23° C. to a solution of intermediate 49.2 (2.15 g, 7.25mmol) in 100 ml of acetone. After agitation overnight, the precipitateformed is filtered off and rinsed with 10 ml of acetone. Thisprecipitate is taken up in a mixture of 100 ml of ethyl acetate and 100ml of a 1M solution of HCl. After decantation. the aqueous phase isreextracted with 25 ml of ethyl acetate. The organic phases arecollected and washed successively with 25 ml of water and 50 ml of saltwater. The organic solution is dried over sodium sulphate, filtered andconcentrated under vacuum in order to produce a yellow powder with ayield of 93%. Melting point: 250-252° C.

[1162] 49.4N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-(4-nitrophenyl)-4-thiazolecarboxamide:

[1163] The experimental protocol used is the same as that described forintermediate 46.3, intermediate 49.3 replacing intermediate 46.2. Theexpected compound is obtained in the form of a yellow powder with ayield of 51%. Melting point: 262-264° C.

[1164] NMR ¹H (acetone d6, 100 MHz, δ): 1.60 (s, 18H, 2 tBu), 6.12 (s,1H, OH), 8.21 (m, 2H, arom. H), 8.50 (s, 4H, arom. H), 8.60 (s, 1H,thiazole), 9.93 (wide s, 1H, CO—NH).

[1165] 49.5N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-(4-aminophenyl)-4-thiazolecarboxamide:

[1166] 3.59 g (16 mmol) of SnCl₂.2H₂O is introduced into a solution ofintermediate 49.4 (1.50 g, 3.18 mmol) in 50 ml of an ethylacetate/ethanol/acetone mixture (2/1/2). The reaction mixture is heatedunder reflux for 5 hours and finally after cooling down, concentrationto one half is carried out under vacuum. The evaporation residue is thenpoured into 50 ml of cold water, the precipitate which forms is dilutedwith 100 ml of ethyl acetate and 25 ml of a saturated solution ofNaHCO₃. The cloudy mixture is filtered on celite and the filtrate isdecanted. The organic phase is washed successively with 50 ml of waterand 50 ml of salt water. After drying over magnesium suphate andfiltration, the organic solution is concentrated under vacuum in orderto produce a bright yellow powder which is purified by washing with anEt₂O/heptane mixture (90/10). The expected compound is obtained in theform of a pale yellow powder with a yield of 55%. Melting point:267-268° C.

[1167] NMR ¹H (CDCl₃, 100 MHz, δ): 1.49 (s, 18H, 2 tBu), 4.00 (wide s,2H, NH₂), 5.11 (s, 1H, OH), 6.72 (m, 2H, arom. H), 7.60 (s, 2H, arom.H), 7.81 (m, 2H, arom. H), 8.05 (s, 1H, thiazole), 9.10 (wide s, 1H,CO—NH).

[1168] 49.6N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-{4-[(imino(2-thienyl)methyl)amino]phenyl}-4-thiazolecarboxamideHydroiodide (49):

[1169] The experimental protocol used is the same as that described forintermediate 33.3, intermediate 49.5 replacing intermediate 33.2. Ayellow powder is obtained with a yield of 27%. Melting point: 270-272°C.

[1170] NMR ¹H (DMSO d6, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 6.89 (s, 1H,OH), 7.41 (m, 1H, arom. H), 7.63 (m, 4H, arom. H), 8.11 (m, 1H, arom.H), 8.20 (m, 1H, arom. H), 8.36 (m, 2H, arom. H), 8.48 (s, 1H, arom. H),9.19 (wide s, 1H, NH⁺), 9.90 (wide s, 1H, NH⁺), 10.02 (s, 1H, CO—NH),11.50 (s, 1H, NH⁺).

[1171] IR: ν_(C═O) (amide): 1660 cm⁻¹; ν_(C═N) (amidine): 1646 cm⁻¹.

Example 50N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine-2-(R)-carboxamideDihydrochloride (50)

[1172] 50.1 1-(1,1-dimethylethyl) and 2-methyl4-(S)-(4-nitrophenoxy)-1,2-(R)-pyrrolidinedicarboxylate:

[1173] 4.38 g (31.5 mmoles) of 4-nitrophenol in solution in 40 ml ofanhydrous N-methyl-2-pyrrolidinone is added dropwise to a suspension of1.26 g (31.5 mmoles) of NaH at 60% in 60 ml of anhydrousN-methyl-2-pyrrolidinone in a three-necked flask cooled down to 0° C.under an inert atmosphere. The reaction is accompanied by a significantrelease of hydrogen. After agitation for one hour at 0° C. 6 g (15mmoles) of 1-(1,1-dimethylethyl) and 2-methyl4-(R)-{[(4-methylphenyl)sulphonyl]oxy}-1,2-(R)-pyrrolidinedicarboxylateis added in one go, agitation is maintained for another 15 hours at 23°C. and the reaction is completed by 5 hours of reflux. After thereaction mixture is returned to 23° C., it is diluted with 150 ml ofethyl acetate and 100 ml of a 1M solution of soda. After decantation,the aquoeus phase is reextracted twice with 50 ml of ethyl acetate. Theorganic phases are collecteed and washed successively with 1N soda(until the excess of 4-nitrophenol of the organic phase disappears),with water until neutrality is achieved and finally with 100 ml of saltwater. After drying over magnesium sulphate and filtration, the organicsolution is concentrated under vacuum in order to produce an oily brownresidue which is purified on a silica column (eluant: heptane/ethylacetate: 8/2). The pure fractions are collected and concentrated undervacuum in order to produce a pale yellow oil with a yield of 83%.

[1174] NMR ¹H (CDCl₃, 100 MHz, δ): 1.41 (s, 9H, tBu), 2.40 (m, 2H, CH₂),3.80 (s, 5H, CH₃+CH₂), 4.50 (m, 1H, CH—N), 5.03 (m, 1H, CH—O), 6.95 (m,2H, arom. H), 8.22 (m, 2H, arom. H).

[1175] 50.2 1,1-dimethylethyl2-(R)-carboxy-4-(S)-(4-nitrophenoxy)-1-pyrrolidinecarboxylate:

[1176] A solution of 2.14 g (38 mmoles) of KOH in 15 ml of water isadded dropwise at 0° C. to a solution of 7 g (19 mmoles) of intermediate50.1 in 100 ml of methanol. The reaction mixture is agitated at 23° C.for 15 hours and finally concentrated to one half under vacuum. Afterdilution with 50 ml of ethyl acetate and 50 ml of 1N soda, the mixtureis decanted. The organic phase is eliminated and the aquoeus phase isacidified cold with 1M HCl, the product is then extracted with 100 ml ofethyl acetate. The organic solution is then washed with 50 ml of waterand 50 ml of salt water. After drying over magnesium sulphate andfiltration, the solution is concentrated under vacuum. A pale yellow oilis obtained with a yield of 66%.

[1177] NMR ¹H (CDCl₃, 100 MHz, δ): 1.45 (s, 9H, tBu), 2.52 (m, 2H, CH₂),3.80 (m, 2H, CH₂), 4.48 (m, 1H, CH—N), 5.03 (m, 1H, CH—O), 5.92 (wide s,CO₂H), 6.92 (m, 2H, arom. H), 8.20 (m, 2H, arom. H).

[1178] 50.3 1,1-dimethylethyl2-(R)-{[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]amino]carbonyl}-4-(S)-(4-nitrophenoxy)-pyrrolidine-1-carboxylate:

[1179] The experimental protocol used is the same as that described forintermediate 46.3, intermediate 50.2 replacing intermediate 46.2. Abeige powder is obtained with a yield of 43%. Melting point: 140-142° C.

[1180] NMR ¹H (CDCl₃, 100 MHz, δ): 1.45 (s, 18H, 2 tBu), 1.50 (s, 9H,tBu), 2.30 (m, 1H, ½CH₂), 2.95 (m, 1H, ½CH₂), 3.75 (m, 2H, CH₂), 4.65(m, 1H, CH—N), 5.10 (m, 2H, CH—O+OH), 6.98 (m, 2H, arom. H), 7.31 (s,2H, arom. H), 8.22 (m, 2H, arom. H), 9.10 (wide s, 1H, CO—NH).

[1181] 50.4 1,1-dimethylethyl2-(R)-{[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]amino]carbonyl}-4-(S)-(4-aminophenoxy)-pyrrolidine-1-carboxylate:

[1182] The experimental protocol used is the same as that described forintermediate 46.4, intermediate 50.3 replacing intermediate 46.3. Afterpurification on a silica column (eluant: heptane/ethyl acetate: 1/1) andconcentration of the pure fractions, the expected compound is obtainedin the form of a beige powder with a yield of 70%. Melting point:104-106° C. NMR ¹H (CDCl₃, 100 MHz, δ): 1.45 (s, 18H, 2 tBu), 1.50 (s,9H, tBu), 1.60 (s, 2H, NH₂), 2.10 (m, 1H, ½CH₂), 2.80 (m, 1H, ½CH₂),3.60 (m, 2H, CH₂), 4.60 (m, 1H, CH—N), 4.85 (m, 1H, CH—O), 5.04 (s, 1H,OH), 6.70 (m, 4H, arom. H), 7.34 (s, 2H, arom. H), 9.10 (wide s, 1H,CO—NH).

[1183] 50.5N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine-2-(R)-carboxamideDihydrochloride (50):

[1184] The experimental protocol used is the same as that described forintermediate 34.4, intermediate 50.4 replacing3-(4-aminobenzyl)-thiazolidine. The free base, obtained in the form of alight yellow powder, is directly deprotected in the presence of 10equivalents of a 4M solution of anhydrous HCl in 1,4-dioxan. Afteragitation for 15 hours, the precipitate formed is filtered, the crystalsare washed with acetone followed by ethyl ether. The expected product isobtained in the form of a pale yellow powder with a yield of 53%.Melting point: 245-247° C.

[1185] NMR ¹H (DMSO d6, 400 MHz, δ): 1.36 (s, 18H, 2 tBu), 2.29 (m, 1H,½CH₂), 2.71 (m, 1H, ½CH₂), 3.42 (m, 1H, ½CH₂), 3.77 (m, 1H, ½CHR), 4.57(m, 1H, CH—N), 5.26 (m, 1H, CH—O), 6.93 (s, 1H, OH), 7.17 (m, 2H, arom.H), 7.37 (m, 1H, arom. H), 7.42 (m, 2H, arom. H), 7.48 (s, 2H, arom. H),8.17 (m, 2H, arom. H), 8.81 (wide s, 1H, NH⁺), 9.03(wide s, 1H, NH⁺),9.78 (wide s, 1H, NH⁺), 10.70 (s, 1H, CO—NH), 10.84 (wide s, 1H, NH⁺),11.50 (wide s, 1H, NH⁺).

[1186] IR: ν_(C═O) (amide): 1681 cm⁻¹; ν_(C═N) (amidine): 1652 cm⁻¹.

Example 51 methyl1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)carbonyl]-4-(S)-{4-[(imino(2-thienyl)methyl)amino]-phenoxy}-pyrrolidine-2-(S)-carboxylateHydrochloride (51)

[1187] 51.1 1-(1,1-dimethylethyl) and 2-methyl4-(S)-(4-nitrophenoxy)-1,2-(S)-pyrrolidinedicarboxylate

[1188] The experimental protocol used is the same as that described forintermediate 50.1, the 1-(1,1-dimethylethyl) and 2-methyl4-(S)-{[(4-methylphenyl)sulphonyl]oxy}-1,2-(R)-pyrrolidinedicarboxylatederivatives being used instead of the 1-(1,1-dimethylethyl) and 2-methyl4-(R)-{[(4-methylphenyl)sulphonyl]oxy}-1,2-(R)-pyrrolidinedicarboxylatederivatives. The expected product is obtained in the form of a whitepowder with a yield of 63%. Melting point: 155-157° C.

[1189] NMR ¹H (DMSO d6, 400 MHz, δ): 1.37 (2 s, 9H, tBu), 2.22 (m, 1H,½CH₂), 2.62 (m, 1H, ½CH₂), 3.45 (m, 1H, ½CH₂), 3.62 (2 s, 3H, OCH₃),3.78 (m, 1H, ½CH₂), 4.42 (m, 1H, CH—N), 5.20 (m, 1H, CH—O), 7.07 (m, 2H,arom. H), 8.20 (m, 2H, arom. H).

[1190] 51.2 Methyl 4-(S)-(4-nitrophenoxy)-pyrrolidine-2-(S)-carboxylate:

[1191] 10 ml (94 mmol) of trifluoroacetic acetic diluted with 10 ml ofdichloromethane is added at 0° C. to a a solution of 3.45 g (9.4 mmol)of intermediate 51.1 in 15 ml of dichloromethane. The reaction mixtureis then agitated for 2 hours at 23° C. and finally it is concentratedunder vacuum. The evaporation residue is diluted with 100 ml ofdichloromethane and the organic solution is washed successively 3 timeswith 20 ml of a saturated solution of Na₂CO₃, twice with 20 ml of waterand finally with 20 ml of salt water. After drying over magnesiumsulphate and filtration, the organic solution is concentrated undervacuum in order to produce a pale yellow oil with a yield of 78%.

[1192] 1.3 Methyl1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)carbonyl]-4-(S)-(4-nitrophenoxy)-pyrrolidine-2-(S)-carboxylate:

[1193] 1.3 g (8.06 mmol) of 1,1′-carbonyldiimidazole is added to asolution of 1.83 g (7.33 mmol) of Trolox in 20 ml of dry THF. Afteragitation for one hour at 23° C., a solution of 1.95 g (7.33 mmoles) ofintermediate 51.2 diluted in 10 ml of dry THF is added dropwise. Thereaction mixture is agitated at 23° C. for 15 hours and finallyconcentrated to dryness under vacuum. The residue is diluted with 100 mlof ethyl acetate and the organic solution is washed twice with 50 ml ofwater and 50 ml of salt water. After drying over magnesium sulphate andfiltration, the organic solution is concentrated under vacuum. Theevaporation residue is purified on a silica gel column (eluant:heptane/ethyl acetate: 6/4). The pure fractions are collected andevaporated under vacuum in order to produce a yellow powder with a yieldof 61%. Melting point: 103-105° C.

[1194] NMR ¹H (CDCl₃, 400 MHz, δ): 1.55-2.50 (m, 16H, Trolox), 2.63 (m,2H, CH₂), 3.60-3.71 (2 s, 3H, OCH₃), 3.85 (m, 2H, CH₂), 4.70-4.88 (2 m,1H, CH—N), 5.02 (m, 1H, CH—O), 6.82 (m, 2H, arom. H), 8.20 (m, 2H, arom.H).

[1195] 51.4 Methyl1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)carbonyl]-4-(S)-(4-aminophenoxy)-pyrrolidine-2-(S)-carboxylate:

[1196] The protocol used is the same as that described for intermediate46.4, intermediate 51.3 replacing intermediate 46.3. The expectedproduct is obtained in the form of a white powder with a yield of 95%.Melting point: 110-i 12° C.

[1197] 51.5 Methyl1-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2-H-[1]-benzopyran-2-yl)carbonyl]-4-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidine-2-(S)-carboxylateHydrochloride (51):

[1198] The protocol used is the same as that described for intermediate34.4, intermediate 51.4 replacing intermediate 34.3. The condensationreaction is carried out in 2-propanol only. After salification, theexpected product is obtained in the form of a pale yellow powder with ayield of 75%. Melting point: 203-206° C.

[1199] NMR ¹H (DMSO d6, 400 MHz, δ): 1.55-2.50 (m, 16H, Trolox), 2.45(m, 2H, CH₂), 3.45-3.60 (2 s, 3H, OCH₃), 3.70 (m, 2H, CH₂), 4.51 (m, 1H,CH—N), 5.02 (m, 1H, CH—O), 7.00 (m, 2H, arom. H), 7.39 (m, 3H, arom. H),8.16 (m, 2H, arom. H), 8.80 (wide s, 1H, NH⁺), 9.75 (wide s, 1H, NH⁺),11.36 (wide s, 1H, NH⁺). IR: ν_(C═O) (amide): 1650 cm⁻¹; ν_(C═N)(amidine): 1611 cm⁻¹.

Example 521-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-pyrrolidineHydrochloride (52)

[1200] 52.11,1-dimethylethyl:3-(R)-[(4-methylphenyl)sulphonyl]oxy)-1-pyrrolidinecarboxylate

[1201] 21.6 g (114 mmol) of p-toluenesulphonyl chloride is added to asolution of 10 g (57 mmol) of (R)-N-Boc-3-pyrrolidinol (prepared in astandard fashion starting from commercial (R)-3-pyrrolidinol) and 13.7ml (171 mmoles) of pyridine in 150 ml of dichloromethane). Afteragitation for 24 hours at 23° C., the reaction mixture is washed with 3times 50 ml of a 1M solution of HCl. After decantation, the organicphase is washed with 50 ml of water followed by 50 ml of salt water andfinally dried over magnesium sulphate, filtred and concentrated undervacuum. The evaporation residue is purified rapidly on a silica column(eluant: heptane/ethyl acetate: 8/2) in order to produce a pale yellowoil with a yield of 67%.

[1202] 52.2 1,1-dimethylethyl3-(S)-(4-nitrophenoxy)-1-pyrrolidine-carboxylate:

[1203] The experimental protocol used is the same as that described forintermediate 50.1, intermediate 52.1 replacing the 1-(1,1-dimethylethyl)2-methyl4-(R)-{[(4-methylphenyl)sulphonyl]oxy}-1,2-(R)-pyrrolidinedicarboxylatederivative. The expected product is obtained in the form of a lightyellow powder with a yield of 77%. Melting point: 112-114° C.

[1204] NMR ¹H (CDCl₃, 100 MHz, δ): 1.45 (s, 9H, tBu), 2.20 (m, 2H, CH₂),3.60 (m, 4H, CH₂—CH₂), 5.00 (m, 1H, CH—O), 6.94 (m, 2H, arom. H), 8.20(m, 2H, arom. H).

[1205] 52.3 3-(S)-(4-nitrophenoxy)pyrrolidine:

[1206] The experimental protocol used is the same as that described forintermediate 51.2, intermediate 52.2 replacing intermediate 51.1. Abrown oil is obtained with a quantitative yield.

[1207] 52.41-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-(S)-(4-nitrophenoxy)pyrrolidine:

[1208] The experimental protocol used is the same as that described forintermediate 51.3, intermediate 52.3 replacing intermediate 51.2. Theexpected product is obtained after chromatography on a silica column(eluant: heptane/ethyl acetate: 7/3). The pure fractions, afterevaporation, produce a beige powder with a yield of 23%. Melting point:176-178° C.

[1209] NMR ¹H (CDCl₃, 400 MHz, δ): 1.52-2.60 (m, 16H, Trolox), 2.62 (m,2H, CH₂), 3.50-4.40 (m, 4H, CH₂—CH₂), 4.80 (m, 1H, CH—O), 6.89 (m, 2H,arom. H), 8.20 (m, 2H, arom. H).

[1210] 52.51-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-(S)-(4-aminophenoxy)pyrrolidine:

[1211] The experimental protocol used is the same as that described forintermediate 46.4, intermediate 52.4 replacing intermediate 46.3. Awhite powder is obtained with a yield of 78%. Melting point: 98-100° C.

[1212] 52.61-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-(S)-{4-[(imino(2-thienyl)methyl)amino]phenoxy}pyrrolidineHydrochloride (52):

[1213] The protocol used is the same as that described for intermediate34.4, intermediate 52.5 replacing intermediate 34.3. The condensationreaction is carried out in 2-propanol only. After salification, theexpected product is obtained in the form of a pale yellow powder with ayield of 85%. Melting point: 195-197° C.

[1214] NMR ¹H (pyridine d5, 400 MHz, δ): 1.52-2.48 (m, 16H, Trolox),2.60-3.05 (m, 2H, CH₂), 3.58-4.42 (m, 4H, CH-₂—CH₂), 4.59-4.90 (m, 1H,CH—O), 6.65 (m, 1H, arom. H), 6.89 (m, 2H, arom. H), 7.01 (m, 1H, arom.H), 7.15 (m, 1H, arom. H), 7.30 (m, 1H, NH⁺), 7.41 (m, 1H, NH⁺), 7.74(m, 2H, arom. H), 8.95 (m, 1H, NH⁺).

[1215] IR: ν_(C═O) (amide): 1650 cm⁻¹; ν_(C═N) (amidine): 1610 cm⁻¹.

Example 533-{[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1-benzopyran-2-yl)carbonyl]amino}-1-{4-[(imino(2-thienyl)methyl)amino]phenyl}pyrrolidine(53)

[1216] 53.13-{[(1,1-dimethylethoxy)carbonyl]amino}-1-(4-nitrophenyl)pyrrolidine:

[1217] The experimental protocol used is the same as that described forintermediate 33.1, 3-(tert-butoxycarbonylamino)pyrrolidine replacingimidazole.

[1218] NMR ¹H (CDCl₃ 100 MHz, δ): 1.45 (s, 9H, tBu), 2.20 (m, 2H, CH₂),3.50 (m, 4H, 2×CH₂—N), 4.35 (m, 1H, CH—N), 4.75 (m, 1H, NH), 6.45 (m,2H, arom. H), 8.10 (m, 2H, arom. H).

[1219] 53.2 3-amino-1-(4-nitrophenyl)pyrrolidine:

[1220] The experimental protocol used is the same as that described forintermediate 51.2, intermediate 53.1 replacing intermediate 51.1.

[1221] NMR ¹H (CDCl₃, 100 MHz, δ): 1.50 (wide s, 2H, NH₂), 2.10 (m, 2H,CH₂), 3.10 (m, 1H, CH), 3.50 (m, 4H, 2×CH₂), 6.40 (m, 2H, arom. H), 8.10(m, 2H, arom. H).

[1222] 53.33-([(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]amino]-1-(4-nitrophenyl)pyrrolidine:

[1223] The experimental protocol used is the same as that described forintermediate 51.3, intermediate 53.2 replacing intermediate 51.2. Ayellow solid is obtained which is used directly in the following stgaewithout further purification.

[1224] NMR ¹H (CDCl₃, 100 MHz, δ): 1.50-2.20 (m, 18H, Trolox+CH₂), 3.45(m, 4H, 2×CH₂), 4.40 (m, 1H, CH), 4.50 (wide s, 1H, NH), 8.15 (m, 2H,arom. H), 8.35 (m, 2H, arom. H).

[1225] 53.43-{[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]amino}-1-(4-aminophenyl)pyrrolidine:

[1226] The experimental protocol used is the same as that described forintermediate 46.4, intermediate 53.3 replacing intermediate 46.3.

[1227] NMR ¹H (CDCl₃, 100 MHz, δ): 1.50-2.50 (m, 18H, Trolox+CH₂), 3.15(m, 4H, 2×CH₂), 4.50 (m, 2H, CH+NH), 6.40 (m, 4H, arom. H).

[1228] 53.53-([(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]amino]-1-{4-[(imino(2-thienyl)methyl)amino-phenyl-pyrrolidine(53):

[1229] The experimental protocol used is the same as that described forintermediate 34.4, intermediate 53.4 replacing intermediate 34.3. Theexpected product is obtained in the form of a yellow powder (free base)with a yield of 81%. Melting point: 135-138° C.

[1230] NMR ¹H (DMSO d6, 400 MHz, δ): 1.39-2.50 (m, 18H, Trolox+CH₂),2.85-3.43 (m, 4H, 2×CH₂), 4.37 (m, 1H, CH), 6.23 (wide s, 2H, NH₂), 6.46(m, 2H, arom. H), 6.73 (m, 2H, arom. H), 7.07 (m, 1H, arom. H), 7.17 (d.½H, ½CONH. J=7.6 Hz), 7.34 (d. ½H, ½CONH. J=7.6 Hz), 7.56 (m, 1H, arom.H), 7.68 (m, 1H, arom. H).

[1231] IR: ν_(C═O) (amide): 1657 cm⁻¹; ν_(C═N) (amidine): 1626 cm⁻¹.

Example 544-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]benzoyl}-N-methyl-1H-imidazole-2-methanamineHydrochloride (54)

[1232] 54.1([3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]carbonyl]methylN-methyl-N-[(phenylmethoxy)carbonyl]glycinate:

[1233] This intermediate is obtained in a standard fashion starting fromCbz-Sarcosine and1-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-bromo-ethanone in thepresence of caesium carbonate in DMF.

[1234] NMR ¹H (CDCl₃, 100 MHz, d): 1.46 (s, 18H, 2 tBu), 3.00 (s, 3H,N—CH₃), 4.20 (m, 2H, O—CH₂—Ph), 5.10-5.40 (m, 4H, CH ₂—N(CH₃)+CO—CH₂—O—CO), 5.80 (s, 1H, OH), 7.30 (m, 5H, arom. H), 7.70 (s, 2H, arom. H).

[1235] 54.24-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-[(phenylmethoxy)carbonyl]-1H-imidazole-2-methanamine:

[1236] This intermediate is obtained, starting from intermediate 54.1,using the same experimental protocol as that described in TetrahedronLett,. 1993. 34. 1901. A pale green powder is obtained with a yield of81%. Melting point: 200-207° C.

[1237] NMR ¹H (CDCl₃, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 3.00 (s, 3H,N—CH₃), 4.50 (m, 2H, O—CH₂—Ph), 5.10 (s, 2H, CH ₂—N—COO), 5.20 (s, 1H,OH), 7.00 (s, 1H, imidazole), 7.20-7.50 (m, 7H, arom. H), 9.90 (s, 1H,NH).

[1238] 54.34-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-[(phenylmethoxy)carbonyl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-2-methanamine:

[1239] 7.1 g (51.2 mmol) of potassium carbonate is added by portions toa mixture of 9.96 ml (56.3 mmol) of 2-(trimethylsilyl)ethoxymethylchloride and 23 g (51.2 ml) of intermediate 54.2 in 200 ml of DMF. Whenthe addition is finished, the reaction mixture is agitated for 3 hoursat 50° C. The solvent is then eliminated under vacuum and the residue isdiluted with 200 ml of ethyl acetate. The organic solution is washedtwice with 100 ml of salt water, dried over magnesium sulphate, filteredand concentrated under vacuum. The evaporation residue is purified on asilica gel column (eluant heptane/ethyl acetate: 1/1). The purefractions are evaporated in order to produce a green oil with a yield of53%.

[1240] NMR ¹H (CDCl₃, 400 MHz, δ): 0.0 (s, 9H, Si(CH₃)₃), 0.9 (m, 2H,CH₂—Si), 1.50 (s, 18H, 2 tBu), 3.00 (s, 3H, N—CH₃), 3.30-3.50 (m, 2H,O—CH ₂—CH₂—Si), 4.70 (s, 2H, CH ₂—N—COO), 5.10 (s, 2H, O—CH₂—Ph), 5.20(s, 2H, imidazole-CH ₂—OSEM), 5.30 (s, 1H, OH), 7.20 (s, 1H, imidazole),7.35 (m, 5H, arom. H), 7.60 (s, 2H, arom. H).

[1241] 54.44-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-1-{[2-(trimethylsilyl)ethoxy]-methyl}-1H-imidazole-2-methanamine:

[1242] The experimental protocol used is the same as that described forintermediate 46.4, intermediate 54.3 replacing intermediate 46.3. Abrown oil is obtained with a yield of 98%.

[1243] NMR ¹H (CDCl₃, 100 MHz, δ): 0.0 (s, 9H, Si(CH₃)₃), 0.9 (m, 2H,CH₂—Si), 1.50 (s, 18H, 2 tBu), 2.50 (s, 3H, N—CH₃), 3.50 (m, 2H, O—CH₂—CH₂—Si), 4.00 (s, 2H, N—CH ₂-imidazole), 5.20 (s, 1H, OH), 5.40 (s,2H, imidazole-CH ₂—OSEM), 7.10 (s, 1H, imidazole), 7.50 (s, 2H, arom.H).

[1244] 54.54-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-nitrobenzoyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazole-2-methanamine:

[1245] A solution of 2.67 g (14.4 mmol) of 4-nitrobenzoic acid chloridein 50 ml of dry THF is added dropwise to a solution of 5.34 g (11.9mmol) of intermediate 54.4 and 2 ml (14.4 mmol) of triethylamine in 50ml of dichloromethane. After agitation for 2 hours at 23° C., themixture is diluted with 100 ml of dichloromethane and the organicsolution is washed with twice 100 ml of salt water. After drying overmagnesium sulphate, the organic phase is filtered and concentrated undervacuum in order to produce a yellow oil which is used as it is in thefollowing stage.

[1246] NMR ¹H (CDCl₃, 400 MHz, δ): 0.0 (s, 9H, Si(CH₃)₃), 0.9 (m, 2H,CH₂—Si), 1.50 (s, 18H, 2 tBu), 3.15 (s, 3H, N—CH₃), 3.50 (m, 2H, O—CH₂—CH₂—Si), 4.80 (s, 2H, N—CH ₂-imidazole), 5.20 (s, 2H, imidazole-CH₂—OSEM), 5.30 (s, 1H, OH), 6.90 (m, 2H, arom. H), 7.15 (s, 1H,imidazole), 7.60 (s, 2H, arom. H), 8.10 (m, 2H, arom. H).

[1247] 54.64-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-nitrobenzoyl)-1H-imidazole-2-methanamine:

[1248] Intermediate 54.5 (7.42 g, 12.5 mmol) is dissolved in 62.4 ml(62.4 mmol) of a 1M solution of tetrabutylammonium fluoride in thepresence of 1.12 g (18.7 mmol) of ethylenediamine. The reaction mixtureis heated under reflux for 5 hours and finally poured directly into 200ml of salt water and diluted with 200 ml of ethyl acetate. The organicphase is decanted, washed with 100 ml of salt water and finally driedover magnesium sulphate, filtered and concentrated under vacuum. Theevaporation residue is purified on a silica column (eluant:dichloromethane+5% of ethanol). The expected product is obtained in theform of a red foam with a yield of 37%.

[1249] NMR ¹H (CDCl₃, 400 MHz, d): 1.50 (s, 18H, 2 tBu), 3.00 (s, 3H,N—CH₃), 4.70 (s, 2H, N—CH ₂-imidazole), 5.20 (s, 1H, OH), 7.10 (s, 1H,imidazole), 7.40-7.60 (m, 4H, arom. H), 8.30 (m, 2H, arom. H), 10.10(wide s, 1H, NH).

[1250] 54.74-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-aminobenzoyl)-1H-imidazole-2-methanamine:

[1251] The experimental protocol used is the same as that described forintermediate 46.4, intermediate 54.6 replacing intermediate 46.3. Anorange solid is obtained with a yield of 52%. Melting point: 129-131° C.

[1252] NMR ¹H (CDCl₃, 400 MHz, δ): 1.50 (s, 18H, 2 tBu), 3.10 (s, 3H,N—CH₃), 3.90 (s, 2H, N—CH ₂-imidazole), 4.70 (s, 2H, NH₂), 5.20 (s, 1H,OH), 6.60 (m, 2H, arom. H), 7.10 (s, 1H, Imidazole), 7.30-7.60 (m, 4H,arom. H), 10.30 (wide s, 1H, NH).

[1253] 54.84-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]benzoyl}-N-methyl-1H-imidazole-2-methanamineHydrochloride (54):

[1254] The experimental protocol used is the same as that described forintermediate 36.3, intermediate 54.7 replacing intermediate 36.2. Alight beige solid is obtained with a yield of 54%. Melting point:250-260° C.

[1255] NMR ¹H (DMSO d6, 400 MHz, δ): 1.50 (s, 18H, 2 tBu), 3.20 (s, 3H,N—CH₃), 5.00 (s, 2H, N—CHR-imidazole), 7.30 (s, 1H, OH), 7.35 (m, 1H,thiophene), 7.50 (m, 4H, arom. H), 7.70 (s, 2H,a. H), 8.00 (s, 1H,Imidazole), 8.20 (m, 2H, thiophene), 9.20 (s, 1H, NH⁺), 10.00 (s, 1H,NH⁺), 11.8 (s, 1H, NH⁺), 14.8 (s, 1H, NH⁺), 15.2 (s, 1H, NH⁺).

[1256] IR: ν_(C═O) (amide): 1635 cm⁻¹; ν_(C═N) (amidine): 1601 cm⁻¹.

Example 55N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-{4-[(imino(2-thienyl)methyl)amino]phenyl}-1H-pyrrole-2-carboxamideHydroiodide (55)

[1257] 55.1 Ethyl 1-(4-nitrophenyl)-1H-pyrrole-2-carboxylate:

[1258] 0.9 g (7.2 mmol) of the methyl ester of pyrrole-2-carboxylic acid(prepared in a standard fashion by the esterification of commercialpyrrole-2-carboxylic acid) diluted with 10 ml of dry DMF is addeddropwise at 0° C., under an inert atmosphere, to a suspension of 0.3 g(7.4 mmol) of NaH at 60% in 15 ml of dry DMF. After agitation for onehour at 23° C., a solution of 1.01 g (7.2 mmol) of 4-fluoronitrobenzenein 10 ml of dry DMF is added dropwise. The reaction mixture is thenheated for 3 hours at 80° C. After the reaction medium has returned to23° C., it is poured into 100 ml of an ice+water mixture and finallydiluted with 200 ml of ethyl acetate. After decantation, the organicphase is washed with 3 times 100 ml of water followed by 100 ml of saltwater. The organic solution is dried over magnesium sulphate, filteredand concentrated under vacuum. The evaporation residue is purified on asilica column (eluant: heptane/ethyl acetate: 9/1). The pure fractionsare collected and evaporated under vacuum in order to produce a paleyellow powder with a yield of 49%.

[1259] 55.2 1-(4-nitrophenyl)-1H-pyrrole-2-carboxylic Acid:

[1260] A solution of 0.5 g (7.1 mmol) of KOH in 5 ml of water is addedto a flask containing a solution of 0.87 g (3.5 mmol) of intermediate55.1 in 20 ml of THF cooled down to 0° C. The reaction mixture isagitated for 24 hours at 55° C. and finally diluted with 100 ml of ethylacetate. After decantation, the organic phase is eliminated and theaqueous phase is cooled down using an ice bath before acidification witha solution of concentrated HCl. The precipitate formed is then filteredand washed twice with 20 ml of water. After drying. the expected productis obtained with a yield of 66%.

[1261] 55.3N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-(4-nitrophenyl)-1H-pyrrole-2-carboxamide:

[1262] The experimental protocol used is the same as that described forintermediate 46.3, intermediate 55.2 replacing intermediate 46.2. Theexpected compound is obtained in the form of a greenish powder with acrude yield of 25%. The product is used such as it is in the followingstage.

[1263] 55.4N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-(4-aminophenyl)-1H-pyrrole-2-carboxamide

[1264] The experimental protocol used is similar to that described forintermediate 46.4, intermediate 55.3 replacing intermediate 46.3. Thereaction is carried out in a dichloromethane/ethanol mixture (1/1). Awhite powder is obtained with a yield of 61%. Melting point: 218-219° C.

[1265] 55.5N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-1-[4-[(imino(2-thienyl)methyl)amino]phenyl]-1H-pyrrole-2-carboxamideHydroiodide (55):

[1266] The experimental protocol used is similar to that described forintermediate 33.3, intermediate 55.4 replacing intermediate 33.2. A paleyellow powder is obtained with a yield of 73%. Melting point: 271-272°C.

[1267] NMR ¹H (DMSO d6, 400 MHz, δ): 1.35 (s, 18H, 2 tBu), 6.36 (s, 1H,OH), 6.78 (s, 1H, arom. H), 7.01 (s, 1H, arom. H), 7.16 (s, 1H, arom.H), 7.45 (m, 7H, arom. H), 8.10 (m, 1H, arom. H), 8.19 (m, 1H, arom. H),9.16 (wide s, 1H, NH⁺), 9.89 (wide s, 2H, CONH+NH⁺), 11.39 (wide s, 1H,NH⁺).

[1268] IR: ν_(C═O) (amide): 1633 cm⁻¹; ν_(C═N) (amidine): 1609 cm⁻¹.

Example 561-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-{[4-[[imino(2-thienyl)methyl]amino]phenyl]carbonyl}-2-imidazolidinoneHydroiodide (56)

[1269] 56.1N-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-(2-chloroethyl)urea:

[1270] 0.17 ml (2 mmol) of chloroethylisocyanate is added to a flaskcontaining a solution of 0.5 g (2 mmol) of intermediate 10.2 in 5 ml ofDMF. The reaction mixture is agitated for 2 hours at 23° C. and finallydiluted with 100 ml of ethyl acetate and 25 ml of water. Afterdecantation, the organic solution is washed with 25 ml of water, twicewith 25 ml of salt water and finally dried over magnesium sulphate.After filtration and evaporation, the residue is taken up in isopentanein order to finally produce the expected product, in the form of a pinksolid, with a yield of 83%. Melting point: 169-171° C.

[1271] NMR ¹H (DMSO d6, 400 MHz, δ): 1.30 (s, 18H, 2 tBu), 3.35 (t, 2H,CH—NH, J=6.0 Hz), 3.60 (t, 2H, CH₂—Cl, J=6.0 Hz), 6.20 (t, 1H, NH—CH₂,J=5.6 Hz), 6.60 (s, 1H, OH), 7.10 (s, 2H, arom. H), 8.30 (s, 1H, NH—Ph).

[1272] 56.21-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-imidazolidinone:

[1273] A solution of 0.22 g (1.93 mmol) of tBuO⁻K⁺ in 2 ml of dry DMF isadded to a solution of 0.56 g (1.93 mmol) of intermediate 56.1 in 10 mlof dry DMF. After agitation for 3 hours at 23° C., the reaction mixtureis diluted with 50 ml of water and 100 ml of ethyl acetate. The organicphase is decanted, washed successively with 50 ml of water and 50 ml ofsalt water, dried over magnesium sulphate, filtered and finallyconcentrated under vacuum. The brown oil thus obtained is taken up inisopropyl ether in order to produce a white powder with a yield of 51%.Melting point: 205-207° C.

[1274] NMR ¹H (DMSO d6, 100 MHz, δ): 1.40 (s, 18H, 2 tBu), 4.60 (m, 2H,CH₂), 4.90 (m, 2H, CH₂), 4.90 (wide s, 1H, NH), 5.00 (s, 1H, OH), 7.15(s, 2H, arom. H).

[1275] 56.31-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-[(4-nitrophenyl)carbonyl]-2-imidazolidinone:

[1276] 1.28 g (6.9 mmol) of 4-nitrobenzoic acid chloride is added byportions to a solution of 1.0 g (3.45 mmol) of intermediate 56.2 in amixture of 20 ml of acetonitrile and 10 ml of THF, followed by 0.71 g(5.15 mmol) of potassium carbonate. After agitation for 3 hours at 23°C., the reaction mixture is diluted with 100 ml of dichloromethane and50 ml of salt water. The organic phase, after decantation. is washedwith 50 ml of salt water and dried over magnesium sulphate. Afterfiltration and concentration under vacuum, the evaporation residue takenup in isopropyl ether in order to produce a yellow solid with a yield of83% after drying. Melting point>260° C.

[1277] NMR ¹H (CDCl₃, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 3.95-4.20 (m,4H, 2 CH₂), 5.20 (s, 1H, OH), 7.20 (s, 2H, arom. H), 7.80 (m, 2H, arom.H), 8.25 (m, 2H, arom. H).

[1278] 56.41-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-[(4-aminophenyl)carbonyl]-2-imidazolidinone:

[1279] The experimental protocol used is similar to that described forintermediate 46.4, intermediate 56.3 replacing intermediate 46.3. Theexpected product is obtained in the form of a white powder with a yieldof 45%. Melting point>260° C.

[1280] NMR ¹H (CDCl₃, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 3.90-4.00 (m,4H, 2 CH₂), 5.15 (s, 1H, OH), 6.60 (m, 2H, arom. H), 7.13 (s, 2H, arom.H), 7.60 (m, 2H, arom. H).

[1281] 56.51-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3-[4-[[imino(2-thienyl)methyl]amino]phenyl]carbonyl}-2-imidazolidinoneHydroiodide (56):

[1282] The experimental protocol used is identical to that described forintermediate 33.3, intermediate 56.4 replacing intermediate 33.2. Theexpected product is obtained in the form of a light beige solid with ayield of 79%. Melting point: 220-260° C.

[1283] NMR ¹H (DMSO d6, 400 MHz, d): 1.30 (s, 18H, 2 tBu), 4.00 (m, 4H,2 CH₂), 6.95 (s, 1H, OH), 7.20 (s, 2H, arom. H), 7.40 (m, 1H thiophene),7.50 (m, 2H, arom. H), 7.70 (m, 2H, arom. H), 8.20 (m, 2H, thiophene),9.20 (wide s, 1H, NH⁺), 9.90 (wide s, 1H, NH⁺), 11.60 (wide s, 1H, NH⁺).

[1284] IR: ν_(C═O) (urea): 1735 cm⁻¹; ν_(C═O) (amide): 1649 cm⁻¹;ν_(C═N) (amidine): 1595 cm⁻¹.

Example 573-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-5-isoxazoleacetamideHydroiodide (57)

[1285] 57.1 3,5-bis-(1,1-dimethylethyl)-N,4-dihydroxy-benzene Carboxime:

[1286] This intermediate is prepared according to an experimentalprotocol described in J. Med. Chem,. 1997, 40, 50-60, starting fromcommercial 3,5-di-tert-butyl-4-hydroxybenzaldehyde. A red foam isobtained with a quantitative yield.

[1287] 57.2 3,5-bis-(1,1-dimethylethyl)-N,4-dihydroxy-benzeneCarboximidoyl Chloride:

[1288] The experimental protocol used is the same as that described inTetrahedron Lett,. 1996, 37 (26), 4455, starting from intermediate 57.1.A beige solid is obtained with a crude yield of 77%. The product is useddirectly in the following stage without additional purification.

[1289] 57.3 Methyl3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-isoxazoleacetate:

[1290] The reaction of intermediate 57.2 with the methyl ester of3-butenoic acid is carried out under the same conditions as thosedescribed in Tetrahedron Lett. 1996, 37 (26), 4455. The expectedcompound is obtained in the form of a brown oil with a yield of 49%.

[1291] NMR ¹H (CDCl₃, 400 MHz, δ): 1.50 (s, 18H, 2 tBu), 2.60 (dd. 1H,½CH₂—C═N, J=16.0 Hz and J=7.8 Hz), 2.90 (dd. 1H, ½CH₂—C═N, J=16.0 Hz andJ=5.8 Hz), 3.10 (dd, 1H, ½CH₂—C═O, J=16.6 Hz and J=6.9 Hz), 3.60 (dd.1H, ½CH₂—C═O, J=16.6 Hz and J=10.2 Hz), 5.10 (m, 1H, CH), 5.50 (s, 1H,OH), 7.50 (s, 2H, arom. H).

[1292] 57.43-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-isoxazoleaceticAcid:

[1293] This intermediate is obtained by the saponification ofintermediate 57.3 according to an experimental protocol described in J.Med. Chem. 1997, 40, 50-60. A white solid is obtained with a yield of74%. Melting point: 229-231° C.

[1294] NMR ¹H (CDCl₃, Hz), 2.90 (dd, 1H, ½CH₂—C═N, J=16.3 Hz and J=6.0Hz), 3.10 (dd. 1H, ½CH₂—C═O, J=16.6 Hz and J=6.9 Hz), 3.50 (dd, 1H,½CH₂—C═O, J=16.6 Hz and J=10.2 Hz), 5.05 (m, 1H, CH), 5.50 (s, 1H, OH),7.45 (s, 2H, arom. H).

[1295] 57.53-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-N-(4-nitrophenyl)-5-isoxazoleacetamide:

[1296] The experimental protocol used is the same as that described inOrg. Prep. Proced. Int. (1975), 7. 215 starting from intermediate 57.4and 4-nitroaniline. A white solid is obtained with a yield of 45%.Melting point: 149-151° C.

[1297] NMR ¹H (CDCl₃, 400 MHz, δ): 1.50 (s, 18H, 2 tBu), 2.70 (m, 1H,½CH₂—C═N), 2.85 (dd, 1H, ½CH₂—C═N, J=15.1 Hz and J=7.5 Hz), 3.20 (dd,1H, ½CH₂—C═O, J=16.7 Hz and J=7.0 Hz), 3.70 (dd, 1H, ½CH₂—C═O, J=16.7 Hzand J=10.1 Hz), 5.05 (m, 1H, CH), 5.50 (s, 1H, OH), 7.45 (s, 2H, arom.H), 7.70 (m, 2H, arom. H), 8.20 (m, 2H, arom. H), 8.50 (s, 1H, NH—CO).

[1298] 57.63-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-N-(4-aminophenyl)-5-isoxazoleacetamide:

[1299] The experimental protocol used is the same as that described forintermediate 49.5, intermediate 57.5 replacing intermediate 49.4. Acolourless oil is obtained with a yield of 80%.

[1300] NMR ¹H (CDCl₃, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 2.60 (dd, 1H,½CH₂—C═N, J=15.0 Hz and J=5.7 Hz), 2.80 (dd, 1H, ½CH₂—C═N, J=15.0 Hz andJ=6.7 Hz), 3.15 (dd, 1H, ½CH₂—C═O, J=16.7 Hz and J=7.2 Hz), 3.50 (dd,1H, ½CH₂—C═O, J=16.7 Hz and J=10.1 Hz), 3.70 (2H, NH₂), 5.10 (m, 1H,CH), 5.60 (s, 1H, OH), 6.60 (m, 2H, arom. H), 7.20 (m, 2H, arom. H),7.50 (s, 2H, arom. H), 8.10 (s, 1H, NH—CO).

[1301] 57.73-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-5-isoxazoleacetamideHydroiodide (57):

[1302] The experimental protocol used is identical to that described forintermediate 33.3, intermediate 57.6 replacing intermediate 33.2. Theexpected product is obtained in the form of a pale yellow powder with ayield of 72%. Melting point>260° C.

[1303] NMR ¹H (DMSO d6, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 2.70 (m, 2H,CH₂—C═N), 3.20 (dd. 1H, ½CH₂—C═O, J=16.8 Hz and J=6.8 Hz), 3.60 (dd, 1H,½CH₂—C═O, J=16.8 Hz and J=10.2 Hz), 5.00 (m, 1H, CH), 7.35 (m, 6H, arom.H+OH), 7.80 (m, 2H, arom. H), 8.20 (m, 2H, thiophene), 8.70 (wide s, 1H,NH⁺), 9.70 (wide s, 1H, NH⁺), 10.30 (s, 1H, NH—CO), 11.20 (wide s, 1H,NH⁺).

[1304] IR: ν_(C═O) (amide): 1650 cm⁻¹; ν_(C═N) (amidine): 1603 cm⁻¹.

Example 584-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2-thiazolemethanamineHydrochloride (58)

[1305] 58.12-{[(1,1-dimethylethoxy)carbonyl]methyl}amino-ethanethioamide:

[1306] The experimental protocol used is identical to that described forintermediate 49.1, N-Boc sarcosinamide (obtained in a standard fashionstarting from commercial sarcosinamide and BocOBoc) is used as startingproduct in place of 4-nitrobenzamide. A white paste is obtained which isused directly in the following stage.

[1307] 58.24-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-[(1,1-dimethylethoxy)carbonyl]-N-methyl-2-thiazolemethanamine:

[1308] The experimental protocol used is the same as that described inJ. Org. Chem. (1995), 60, 5638-5642, starting from intermediate 58.1 and1-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-bromo-ethanone. A brownoil is obtained.

[1309] NMR ¹H (CDCl₃, 400 MHz, δ): 1.50 (m, 27H, 3 tBu), 3.00 (s, 3H,N—CH₃), 4.70 (s, 2H, CH₂), 5.30 (s, 1H, OH), 7.25 (s, 1H, thiazole),7.70 (s, 2H, arom. H).

[1310] 58.34-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-2-thiazolemethanamine:

[1311] 2.3 ml (29 mmol) of TFA is added dropwise at 0° C. to a solutionof 2.5 g (5.8 mmol) of intermediate 58.2 and 2 ml (1.6 mmol) oftriethylsilane in 50 ml of dichloromethane. After agitation for onehour, the reaction mixture is concentrated under vacuum and the residueis diluted with 100 ml of ethyl acetate and 50 ml of a saturatedsolution of NaHCO₃. After agitation and decantation, the organic phaseis dried over magnesium sulphate, filtered and concentrated undervacuum. The residue is taken up in heptane in order to produce a whitesolid, after drying, with a yield of 73%. Melting point: 136° C.

[1312] NMR ¹H (CDCl₃, 400 MHz, δ): 1.50 (s, 18H, 2 tBu), 2.60 (s, 3H,N—CH₃), 4.20 (s, 2H, CH₂), 5.30 (s, 1H, OH), 7.20 (s, 1H, thiazole),7.70 (s, 2H, arom. H).

[1313] 58.44-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-nitrophenyl)-2-thiazolemethanamine:

[1314] The experimental protocol used is the same as that described forintermediate 33.1, intermediate 58.3 replacing imidazole. A yellow solidis obtained with a yield of 23%. Melting point: 199-201° C.

[1315] NMR ¹H (DMSO d6, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 3.25 (s, 3H,N—CH₃), 5.10 (s, 2H, CH₂), 6.95 (m, 2H, arom. H), 7.10 (s, 1H, OH), 7.60(s, 2H, arom. H), 7.80 (s, 1H, thiazole), 8.05 (m, 2H, arom. H).

[1316] 58.54-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-aminophenyl)-2-thiazolemethanamine:

[1317] The experimental protocol used is the same as that described forintermediate 49.5, intermediate 58.4 replacing intermediate 49.4. Theexpected product is obtained in the form of a beige foam with a yield of71%.

[1318] NMR ¹H (DMSO d6, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 2.90 (s, 3H,N—CH₃), 4.50 (wide s, 2H, NH₂), 4.60 (s, 2H, CH₂), 6.50 (m, 2H, arom.H), 6.60 (m, 2H, arom. H), 7.10 (s, 1H, OH), 7.60 (s, 2H, arom. H), 7.70(s, 1H, thiazole).

[1319] 58.64-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-2-thiazolemethanamineHydrochloride (58):

[1320] The experimental protocol used is the same as that described forintermediate 36.3, intermediate 58.5 replacing intermediate 36.2. Awhite powder is obtained with a yield of 67%. Melting point: 157-160° C.

[1321] NMR ¹H (DMSO d6, 400 MHz, δ): 1.50 (s, 18H, 2 tBu), 3.15 (s, 3H,N—CH₃), 5.00 (s, 2H, CH₂), 6.95 (m, 2H, arom. H), 7.15 (s, 1H, OH), 7.20(m, 2H, arom. H), 7.40 (m, 1H, thiophene), 7.65 (s, 2H, arom. H), 7.75(s, 1H, thiazole), 8.15 (m, 2H, thiophene), 8.70 (wide s, 1H, NH⁺), 9.70(wide s, 1H, NH⁺), 11.30 (wide s, 1H, NH⁺).

[1322] IR: ν_(C═O) (amide): 1648 cm⁻¹; ν_(C═N) (amidine): 1611 cm⁻¹.

Example 594-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-1H-imidazole-2-methanamineHydrochloride (59)

[1323] 59.14-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-nitrophenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl]-1H-imidazole-2-methanamine:

[1324] The experimental protocol used is the same as that described forintermediate 33.1, intermediate 54.4 replacing imidazole. A yellow solidis obtained with a yield of 53%. Melting point: 149-151° C.

[1325] NMR ¹H (CDCl₃, 400 MHz, δ): 0.0 (s, 9H, Si(CH₃)₃), 0.9 (t, 2H,CH₂—Si, J=8.4 Hz), 1.50 (s, 18H, 2 tBu), 3.15 (s, 3H, N—CH₃), 3.50 (t,2H, O—CH ₂—CH₂—Si, J=8.4 Hz), 4.80 (s, 2H, N—CH ₂-imidazole), 5.20 (s,2H, imidazole-CH ₂—OSEM), 5.25 (s, 1H, OH), 6.90 (m, 2H, arom. H), 7.10(s, 1H, imidazole). 7.60 (s, 2H, arom. H), 8.15 (m, 2H, arom. H).

[1326] 59.24-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-nitrophenyl)-1H-imidazole-2-methanamine:

[1327] The experimental protocol used is the same as that described forintermediate 54.6, intermediate 59.1 replacing intermediate 54.5. Ayellow solid is obtained with a yield of 44%. Melting point: 209-211° C.

[1328] NMR ¹H (CDCl₃, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 3.20 (s, 3H,N—CH₃), 4.70 (s, 2H, CH₂), 6.80-7.10 (m, 3H, arom. H), 7.20-7.60 (m, 3H,arom. H+OH), 8.10 (m, 2H, arom. H), 12.00 (s, 1H, NH).

[1329] 59.34-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-N-(4-aminophenyl)-1H-imidazole-2-methanamine:

[1330] The experimental protocol used is the same as that described forintermediate 46.4, intermediate 59.2 replacing intermediate 46.3. Abeige foam is obtained with a yield of 67%.

[1331] NMR ¹H (CDCl₃, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 2.80 (s, 3H,N—CH₃), 4.20 (s, 2H, CH₂), 4.30-4.70 (m, 3H, NH₂+NH imidazole), 5.00 (s,1H, OH), 6.50 (m, 2H, arom. H), 6.70 (m, 2H, arom. H), 6.80 (s, 1H,imidazole), 7.40 (s, 2H, arom. H).

[1332] 59.44-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-{4-[(imino(2-thienyl)methyl)amino]phenyl}-N-methyl-1H-imidazole-2-methanamineHydrochloride (59):

[1333] The experimental protocol used is the same as that described forintermediate 36.3, intermediate 59.3 replacing intermediate 36.2. Ayellow powder is obtained with a yield of 86%. Melting point: 195-200°C.

[1334] NMR ¹H (DMSO d6, 400 MHz, δ): 1.50 (s, 18H, 2 tBu), 3.20 (s, 3H,N—CH₃), 5.00 (s, 2H, CH₂), 7.00 (m, 2H, arom. H), 7.20 (m, 2H, arom. H),7.40 (m, 2H, thiophene+OH), 7.60 (s, 2H, arom. H), 7.90 (s, 1H,imidazole), 8.20 (m, 2H, thiophene), 8.70 (wide s, 1H, NH⁺), 9.70 (wides, 1H, NH⁺), 11.40 (wide s, 1H, NH⁺), 14.60 (wide s, 1H, NH⁺), 15.60(wide s, 1H, NH⁺).

[1335] IR: ν_(C═O) (amide): 1646 cm⁻¹; ν_(C═N) (amidine): 1612 cm⁻¹.

Example 603-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-{2-{4-[(imino(2-thienyl)methyl)amino]phenoxyethyl}isoxazole (60)

[1336] 60.13-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-isoxazoleethanol:

[1337] 0.09 g (2.4 mmol) of LiAlH₄ is added in small portions to asolution of 0.69 g (2.1 mmol) of intermediate 25.3 in 15 ml of dry THF,cooled down to 0° C. After agitation for one hour at 23° C., thereaction mixture is cooled down using an ice bath and the excess hydrideis destroyed by the addition of water (5 ml). The product is extractedusing twice 25 ml of ethyl ether. The organic phase is washed twice with10 ml of salt water, dried over magnesium sulphate, filtered andconcentrated under vacuum. The residue is purified on silica (eluant:heptane/ethyl acetate: 1/1). A white foam is obtained with a yield of58%.

[1338] NMR ¹H (DMSO d6, 100 MHz, δ): 1.40 (s, 18H, 2 tBu), 1.60-1.80 (m,2H, CH ₂—CH₂—O), 3.05 (m, 1H, ½CH₂ isoxazoline), 3.40 (m, 1H, ½CH₂isoxazoline), 3.50 (m, 2H, CH₂—CH ₂—O), 4.60 (s, 1H, OH), 4.70 (m, 1H,CH isoxazoline), 7.40 (wide s, 3H, arom. H+OH).

[1339] 60.23-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-[2-(4-nitrophenoxy)ethyl]isoxazole:

[1340] A mixture composed of 0.37 g (1.58 mmol) of intermediate 60.1,0.5 ml of Aliquat 336, 0.18 g (1.27 mmol) of 4-fluoronitrobenzene and0.071 g (1.27 mmol) of KOH in 2 ml of toluene is heated at 80° C. for 2hours. After the reaction mixture has returned to 23° C., it is dividedbetween 50 ml of dichloromethane and 20 ml of water. After decantation,the organic phase is washed with 20 ml of water followed by 20 ml ofsalt water. The organic solution is then dried over magnesium sulphate,filtered and concentrated under vacuum. The evaporation residue ispurified on a silica column (eluant: heptane/ethyl acetate: gradient10/0 up to 0/10). A white powder is obtained with a yield of 60%.Melting point: 151-153° C.

[1341] NMR ¹H (CDCl₃, 400 MHz, d): 1.50 (s, 18H, 2 tBu), 2.15 (m, 2H, CH₂—CH₂—O), 3.10 (dd, 1H, ½CH₂ isoxazoline, J=16.3 Hz and J=6.65 Hz), 3.50(dd, 1H, ½CH₂ isoxazoline, J=16.3 Hz and J=10.4 Hz), 4.10-4.30 (m, 2H,CH₂—CH ₂—O), 5.00 (m, 1H, CH isoxazoline), 5.50 (s, 1H, OH), 6.90 (m,2H, arom. H), 7.50 (s, 2H, arom. H), 8.20 (m, 2H, arom. H).

[1342] 60.33-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-[2-(4-aminophenoxy)ethyl]isoxazole:

[1343] The experimental protocol used is the same as that described forintermediate 49.5, intermediate 60.2 replacing intermediate 49.4. Awhite powder is obtained with a yield of 60%. Melting point: 129-131° C.

[1344] NMR ¹H (DMSO d6, 400 MHz, δ): 1.35 (s, 18H, 2 tBu), 2.00 (m, 2H,CH ₂—CH₂—O), 3.15 (dd, 1H, ½CH₂ isoxazoline, J=16.7 Hz and J=7.5 Hz),3.40 (dd, 1H, ½CH₂ isoxazoline, J=16.7 Hz and J=10.5 Hz), 3.90 (m, 2H,CH₂—CH ₂—O), 4.60 (s, 2H, NH₂), 4.70 (m, 1H, CH isoxazoline), 6.50 (m,2H, arom. H), 6.70 (m, 2H, arom. H), 7.40 (s, 3H, arom. H+OH).

[1345] 60.43-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-4,5-dihydro-5-{2-{4-[(imino(2-thienyl)methyl)amino]phenoxy}ethyl}isoxazole(60):

[1346] The experimental protocol used is the same as that described forintermediate 36.3, intermediate 60.3 replacing intermediate 36.2. Awhite solid is obtained with a yield of 32%. Melting point: 240-245° C.

[1347] NMR ¹H (DMSO d6, 400 MHz, δ): 1.40 (s, 18H, 2 tBu), 2.15 (m, 2H,CH ₂—CH₂—O), 3.20 (dd, 1H, ½CH₂ isoxazoline, J=16.65 Hz and J=7.35 Hz),3.50 (dd, 1H, ½CH₂ isoxazoline, J=16.65 Hz and J=10.3 Hz), 4.20 (wide s,2H, CH₂—CH ₂—O), 4.90 (m, 1H, CH isoxazoline), 7.20 (m, 2H, arom. H),7.40 (m, 6H, arom. H+OH), 8.20 (m, 2H, thiophene), 8.80 (wide s, 1H,NH⁺), 9.80 (wide s, 1H, NH⁺), 11.40 (wide s, 1H, NH⁺).

[1348] IR: ν_(C═O) (amide): 1655 cm⁻¹; ν_(C═N) (amidine): 1618 cm⁻¹.

Example 611-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]amino}-carbonyl}-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidineHydrochloride (61)

[1349] 61.1 1-(diphenylmethyl)-3-(4-nitrophenoxy)azetidine:

[1350] 0.5 g (2 mmol) of 1-(diphenylmethyl)-3-hydroxyazetidine is addedunder an argon atmosphere to a suspension of 0.06 g (2.3 mmol) of NaH in20 ml of dry THF. After agitation for one hour at 23° C., a solution of0.29 g (2.1 mmol) of 4-fluoronitrobenzene in 5 ml of dry THF is addeddropwise to the reaction mixture. Agitation is maintained for another 2hours at 23° C. and the whole is finally poured into 25 ml of water. Theproduct is extracted twice with 25 ml of ethyl acetate, the organicphase is then washed twice with 25 ml of salt water, dried overmagnesium sulphate, filtered and concentrated under vacuum. The productis purified on a silica column (eluant: 12% of ethyl acetate inheptane). The pure fractions are evaporated in order to produce acolourless oil with a yield of 40%.

[1351] NMR ¹H (CDCl₃, 400 MHz, d): 3.20 (m, 2H, azetidine), 4.50 (s, TH,CH-(Ph)₂), 4.80 (m, 2H, azetidine), 4.90 (m, 1H, CH—O), 6.80 (m, 2H,arom. H), 7.20-7.50 (in, 10H, arom. H), 8.20 (m, 2H, arom. H).

[1352] 61.2 1-(diphenylmethyl)-3-(4-aminophenoxy)azetidine:

[1353] The experimental protocol used is the same as that described forintermediate 49.5, intermediate 61.1 replacing intermediate 49.4. Acolourless oil is obtained with a yield of 75%.

[1354] NMR ¹H (CDCl₃, 400 MHz, δ): 3.10 (m, 2H, azetidine), 3.40 (wides, 2H, NH₂), 4.40 (s, 1H, CH—(Ph)₂), 4.70 (m, 2H, azetidine), 4.75 (m,1H, CH—O), 6.60 (s, 4H, arom. H), 7.10-7.40 (m, 10H, arom. H).

[1355] 61.31-(diphenylmethyl)-3-{4-[(1,1-dimethylethoxy)carbonyl]aminophenoxy}azetidine:

[1356] Protection of the amine is carried out in a standard fashion withBocOBoc in the presence of triethylamine in dichloromethane. A whitesolid is obtained with a yield of 77%. Melting point: 149-151° C.

[1357] NMR ¹H (DMSO d6, 400 MHz, δ): 1.40 (s, 9H, tBu), 2.90 (wide s,2H, azetidine), 3.60 (wide s, 2H, azetidine), 4.50 (s, 1H, CH—(Ph)₂),4.70 (m, 1H, CH—O), 6.70 (m, 2H, arom. H), 7.10-7.60 (m, 12H, \rom. H),9.10 (s, 1H, NH).

[1358] 61.4 3-{4-[(1,1-dimethylethoxy)carbonyl]aminophenoxy}azetidine:

[1359] The experimental protocol used is the same as that described forintermediate 46.4 except for the hydrogenation catalyst which isreplaced by Pd(OH)₂. A white solid is obtained with a yield of 78%.Melting point 184-186° C.

[1360] NMR ¹H (DMSO d6, 400 MHz, δ): 1.50 (s, 9H, tBu), 3.50 (m, 2H,azetidine), 3.70 (m, 2H, azetidine), 4.90 (m, 1H, CH—O), 6.70 (m, 2H,arom. H), 7.30 (m, 2H, arom. H), 9.10 (s, 1H, NH).

[1361] 61.51-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]amino}carbonyl}-3-{4-[(1,1-dimethylethoxy)carbonyl]aminophenoxy}azetidine:

[1362] A solution of 0.6 g (2.7 mmol) of intermediate 42.2 in 10 ml ofdichloromethane is added dropwise, over one hour, to a solution of 0.27g (0.9 mmol) of triphosgene in 6 ml of dichloromethane. After agitationfor 5 minutes at 23° C., a solution of 0.72 g (2.7 mmol) of intermediate61.4 and 0.52 ml (3 mmol) of diisopropylethylamine in 6 ml ofdichloromethane is added in one go. The reaction mixture is agitated for2 hours at 23° C. and finally evaporated to dryness under vacuum. Theresidue is diluted in 50 ml of ethyl acetate and this organic solutionis washed twice with 25 ml of water followed by 25 ml of salt water.After drying over magnesium sulphate and filtration, the organicsolution is concentrated under vacuum. The residue is purified on asilica column (eluant: heptane/ethyl acetate: 7/3). A white solid isobtained with a yield of 61%. Melting point: 224-226° C.

[1363] NMR ¹H (DMSO d6, 400 MHz, δ): 1.35 (s, 18H, 2 tBu), 1.45 (s, 9H,tBu), 3.80 (m, 2H, azetidine), 4.30 (m, 2H, azetidine), 4.90 (m, 1H,CH—O), 6.60 (s, 1H, OH), 6.70 (m, 2H, arom. H), 7.20 (s, 2H, arom. H),7.35 (m, 2H, arom. H), 8.20 (s, 1H, NH urea), 9.10 (s, 1H, NH).

[1364] 61.61-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]amino}carbonyl}-3-(4-aminophenoxy)azetidine:

[1365] The experimental protocol used is the same as that described forintermediate 58.3, intermediate 61.5 replacing intermediate 58.2. Awhite solid is obtained with a yield of 93%. Melting point: 225-227° C.

[1366] NMR ¹H (DMSO d6, 400 MHz, δ): 1.30 (s, 18H, 2 tBu), 3.80 (m, 2H,azetidine), 4.30 (m, 2H, azetidine), 4.70 (wide s, 2H, NH₂), 4.85 (m,1H, CH—O), 6.40-6.70 (m, 5H, arom. H+OH), 7.25 (s, 2H, arom. H), 8.20(s, 1H, NH urea).

[1367] 61.71-{[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]amino}carbonyl}-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidineHydrochloride (61):

[1368] The experimental protocol used is the same as that described forintermediate 36.3, intermediate 61.6 replacing intermediate 36.2. Awhite solid is obtained with a yield of 16%. Melting point: 235-240° C.

[1369] NMR ¹H (DMSO d6, 400 MHz, δ): 1.30 (s, 18H, 2 tBu), 3.90 (m, 2H,azetidine), 4.40 (m, 2H, azetidine), 5.10 (m, 1H, CH—O), 6.60 (s, 1H,OH), 6.90-7.50 (m, 7H, arom. H), 8.20 (n, 2H, thiophene), 8.30 (s, 1H,NH urea), 8.80 (s, 1H, NH⁺), 9.80 (s, 1H, NH⁺), 11.50 (s, 1H, NH⁺).

[1370] IR: ν_(C═O) (urea): 1660 cm⁻¹; ν_(C═N) (amidine): 1640 cm⁻¹.

Example 621-(2-hydroxy-5-methoxybenzoyl)-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidineHydrochloride (62)

[1371] 62.11-(2-hydroxy-5-methoxybenzoyl)-3-{4-[α]1-dimethylethoxy)carbonyl]-aminophenoxy}azetidine:

[1372] Condensation of 2-hydroxy 5-methoxybenzoic acid and ofintermediate 61.4 is carried out under the same experimental conditionsas those described for intermediate 40.1. A white solid is obtained witha yield of 62%. Melting point: 152-153° C.

[1373] NMR ¹H (DMSO d6, 400 MHz, δ): 1.50 (s, 9H, tBu), 3.70 (s, 3H,OCH₃), 4.00-4.80 (m, 4H, azetidine), 5.00 (m, 1H, CH—O), 6.70-6.90 (m,5H, arom. H), 7.30 (m, 2H, arom. H), 9.1 (s, 1H, OH), 10.65 (s, 1H, NH).

[1374] 62.2 1-(2-hydroxy-5-methoxybenzoyl)-3-aminophenoxy-azetidine:

[1375] The experimental protocol used is the same as that described forintermediate 58.3, intermediate 62.1 replacing intermediate 58.2. Ayellow oil is obtained with a yield of 90%.

[1376] NMR ¹H (DMSO d6, 400 MHz, δ): 3.25 (wide s, 2H, NH₂), 3.80 (s,3H, OCH₃), 4.20-4.90 (m, 4H, azetidine), 4.95 (m, 1H, CH—O), 6.60-7.00(m, 7H, arom. H), 11.35 (wide s, 1H, OH).

[1377] 62.31-(2-hydroxy-5-methoxybenzoyl)-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidineHydrochloride (62):

[1378] The experimental protocol used is the same as that described forintermediate 36.3, intermediate 62.2 replacing intermediate 36.2. Awhite powder is obtained with a yield of 44%. Melting point: 165-166° C.

[1379] NMR ¹H (DMSO d6, 400 MHz, δ): 3.70 (s, 3H, OCH₃), 4.00-4.80 (m,4H, azetidine), 5.15 (m, 1H, CH—O), 6.80-7.10 (m, 5H. arom. H), 7.40 (m,3H, arom. H), 8.20 (m, 2H, thiophene), 8.75 (wide s, 1H, NH⁺), 9.80(wide s, 1H, NH⁺), 10.60 (s, 1H, OH), 11.50 (wide s, 1H, NH⁺).

[1380] IR: ν_(C═O) (amide): 1655 cm⁻¹; ν_(C═N) (amidine): 1612 cm⁻¹.

Example 631-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-4-{4-[(imino(2-thienyl)methyl)amino]phenoxy}-piperidineHydrochloride (63)

[1381] 63.1 1,1-dimethylethyl4-(4-nitrophenoxy)-1-piperidinecarboxylate:

[1382] A solution of 2.01 g (10 mmol) of N-Boc-4-hydroxypiperidine(prepared in a standard fashion starting from commercial4-hydroxypiperidine) in 10 ml of dry THF is added dropwise to a solutionof 1.23 g (11 mmol) of tBuO⁻K⁺ in 10 ml of dry THF in a three neckedflask, under an inert atmosphere, cooled by an ice bath. After agitationfor 30 minutes at 0° C., a solution of 1.06 ml (10 mmol) of4-fluoronitrobenzene in 10 ml of dry THF is added dropwise. The reactionmixture is agitated for 5 hours at 23° C. and finally poured into 25 mlof a water+ice mixture. The product is extracted using 50 ml of ethylacetate. After decantation, the organic phase is washed twice with 25 mlof water and 25 ml of salt water. The organic solution is dried overmagnesium sulphate, followed by filtration and concentration of thefiltrate under vacuum to produce a residue which is purified on a silicacolumn (eluant: heptane/ethyl acetate: 8/2). The pure fractions arecollected and evaporated under vacuum. The expected product is obtainedin the form of a pale yellow powder with a yield of 47%. Melting point:97-98° C.

[1383] 63.2 4-(4-nitrophenoxy)piperidine:

[1384] The experimental protocol used is the same as that described forintermediate 51.2, intermediate 63.1 replacing intermediate 51.1. Ayellow oil is obtained with a yield of 87%.

[1385] NMR ¹H (CDCl₃, 100 MHz, δ): 1.58 (s, 1H, NH), 1.59-2.19 (m, 4H,CH₂—CH₂), 2.65-3.30 (m, 4H, CH₂—CH₂), 4.51 (m, 1H, CH—O), 6.98 (m, 2H,arom. H), 8.21 (m, 2H, arom. H).

[1386] 63.31-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-4-(4-nitrophenyl)piperidine:

[1387] The experimental protocol used is the same as that described forintermediate 51.3, intermediate 63.2 replacing intermediate 51.2. A paleyellow powder is obtained with a crude yield of 83%. The product issufficiently pure to be used directly in the following stage.

[1388] 63.41-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-4-(4-aminophenyl)piperidine:

[1389] The experimental protocol used is similar to that described forintermediate 46.4, intermediate 63.3 replacing intermediate 46.3. Thereaction is carried out in a dichloromethane/ethanol mixture (1/1). Awhite powder is obtained with a yield of 77%. Melting point: 153-154° C.

[1390] NMR ¹H (CDCl₃+D₂O, 400 MHz, δ): 1.60-2.18 (m, 18H, CH₂+Trolox),2.52-2.81 (m, 2H, CH₂), 3.41-4.28 (m, 5H, 2×CH₂+CH—O), 6.63 (m, 2H,arom. H), 6.74 (m, 2H, arom. H).

[1391] 63.51-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-4-[4-[(imino(2-thienyl)methyl)amino]phenoxy}piperidineHydrochloride (63):

[1392] The protocol used is the same as that described for intermediate34.4, intermediate 63.4 replacing intermediate 34.3. The condensationreaction is carried out in 2-propanol only. After salification, theexpected product is obtained in the form of a yellow powder with a yieldof 25%. Melting point: decomposition from 170° C.

[1393] NMR ¹H (DMSO d6, 400 MHz, δ): 1.50-2.10 (m, 18H, CH₂+Trolox),2.40-2.65 (m, 2H, CH₂), 3.13-4.37 (m, 4H, 2×CH₂), 4.64 (m, 1H, CH—O),7.11 (m, 2H, arom. H), 7.35 (m, 2H, arom. H), 7.57 (s, 1H, arom. H),8.17 (m, 2H, arom. H), 8.74 (wide s, 1H, NH⁺), 9.76 (wide s, 1H, NH⁺),11.42 (wide s, 1H, NH⁺).

[1394] IR: ν_(C═O) (amidine): 1611 cm⁻¹.

Example 641-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-{4-[(imino(2-thienyl)methyl)amino]-phenoxy}azetidineHydrochloride (64)

[1395] 64.11-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-[4-[(1,1-dimethylethoxy)carbonyl]aminophenoxy}azetidine:

[1396] The condensation of Trolox and intermediate 51.4 is carried outunder the same experimental conditions as those described forintermediate 40.1. A white solid is obtained with a yield of 98%.Melting point: 182-183° C.

[1397] NMR ¹H (CDCl₃, 400 MHz, δ): 1.50 (s, 9H, tBu), 1.60-2.60 (m, 16H,Trolox), 3.90-4.90 (m, 5H, azetidine), 6.40 (s, 1H, OH), 6.65 (m, 2H,arom. H), 7.20-7.30 (m, 3H, arom. H+NH).

[1398] 64.21-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-aminophenoxy-azetidine:

[1399] The experimental protocol used is the same as that described forintermediate 58.3, intermediate 64.1 replacing intermediate 58.2. Awhite foam is obtained with a yield of 43%.

[1400] NMR ¹H (CDCl₃, 400 MHz, δ): 1.60-2.60 (m, 16H, Trolox), 3.50(wide s, 2H, NH₂), 3.90-4.90 (m, 5H, azetidine), 6.50-6.70 (m, 4H, arom.H).

[1401] 64.31-[(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-[1]-benzopyran-2-yl)carbonyl]-3-{4-[(imino(2-thienyl)methyl)amino]phenoxy}azetidineHydrochloride (64):

[1402] The experimental protocol used is the same as that described forintermediate 36.3, intermediate 64.2 replacing intermediate 36.2. Awhite powder is obtained with a yield of 56%. Melting point: 190-195° C.

[1403] NMR ¹H (DMSO d6, 400 MHz, δ): 1.60-2.50 (m, 16H, Trolox),3.60-5.00 (m, 5H, azetidine), 6.90 (m, 2H, arom. H), 7.30 (m, 3H, arom.H), 8.15 (m, 2H, thiophene), 8.80 (wide s, 1H, NH⁺), 9.80 (wide s, 1H,NH⁺), 11.50 (wide s, 1H, NH⁺).

[1404] IR: ν_(C═O) (amide): 1647 cm⁻¹; ν_(C═N) (amidine): 1611 cm⁻¹.

Example 65N-{4-[({[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}amino)methyl]phenyl}thiophene-2-carboximidamide(65)

[1405] 65.1 benzyl{4-[3,5-di(tert-butyl)-4-hydroxyphenyl]-1,3-thiazol-2-yl}methylcarbamate:

[1406] This compound is produced according to an experimental protocoldescribed for intermediates 58.1 and 58.2, using Z-Gly-NH₂ in place ofthe N-Boc sarcosinamide. The expected compound is obtained in the formof a pale yellow oil with a yield of 99%. MH+=453.20

[1407] 65.24-[2-(aminomethyl)-1,3-thiazol-4-yl]-2,6-(di-tert-butyl)phenol:

[1408] 0.1 ml of a 40% solution of potassium hydroxide was addeddropwise to a solution of 0.106 g (1.1 mmol) of Intermediate 65.1 in 10ml of methanol. After overnight stirring under reflux, the reactionmixture was concentrated under vacuum and the residue diluted withdichloromethane, washed with a 1N solution of HCl and then with 50 ml ofa saturated solution of NaCl. The organic phase once decanted was driedover MgSO₄, filtered and concentrated under vacuum. The expected productwas obtained after chromatography on a silica gel column (eluent: 5%ethanol in dichloromethane) as a brown foam with a yield of 76%.MH⁺=319.29.

[1409] 65.3 2,6-di-tert-butyl-4-(2-([(4-nitrobenzyl)amino]methyl]-1,3-thiazol-4-yl)phenol:

[1410] Under an argon atmosphere, a mixture of 0.175 g (0.55 mmol) ofIntermediate 65.2, 0.075 g (0.494 mmol) of 4-nitrobenzaldehyde and 0.3 gactivated powdered molecular sieves (3A) in 10 ml MeOH was stirred 18hours before addition of 0.021 g (0.55 mmol) NaBH₄. Stirring wascontinued for 6 hours, the reaction mixture was then filtered and themolecular sieves rinsed with CH₂Cl₂. The filtrate was washed with brineand the organic layer dried over MgSO₄. After filtration and evaporationof the solvent, the residue was flash chromatographed usingheptane/EtOAc (1/1) as eluent to yield 0.1 g (40%) of a yellow oil whichslowly crystallizes.

[1411] 65.44-(2-{[(4-aminobenzyl)amino]methyl}-1,3-thiazol-4-yl)-2,6-di-tert-butylphenol:

[1412] The experimental protocol used is essentially the same asdescribed for Intermediate 18.2, starting from Intermediate 65.3. Alight yellow gum was obtained (83%), pure enough to be used directly inthe next step without further purification.

[1413] 65.5N-{4-[({[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}amino)methyl]phenyl}thiophene-2-carboximidamide:

[1414] The experimental protocol used is the same as described forIntermediate 1.3, starting from Intermediate 65.4. The free base waspurified by flash chromatography using CH₂Cl₂/EtOH (95/5) as eluent toyield a yellow oil (35%). MH⁺: 533.30.

Example 66N-{3-[({[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}amino)methyl]phenyl}thiophene-2-carboximidamide(66)

[1415] The experimental protocol used is the same as that described forExample 65, except that 3-nitrobenzaldehyde replaced4-nitrobenzaldehyde. The free base was obtained as an orange foam. MH⁺:533.20.

Example 67N-(4-{[{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}(methyl)amino]methyl}phenyl)thiophene-2-carboximidamide(67)

[1416] 67.1 2,6-di-tert-butyl-4-(2-[methyl(4-nitrobenzyl)amino]methyl]-1,3-thiazol-4-yl)phenol:

[1417] To a cold solution of 1.1 g (3.31 mmol) of4-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-N-methyl-2-thiazolemethanamine(Intermediate 58.3) and 0.7 ml (4.96 mmol) of Et₃N in 50 ml CH₂Cl₂ wasadded portionwise 1.07 g (4.96 mmol) of 4-nitrobenzylbromide. Afterovernight stirring, another portion (0.35 g; 1.65 mmol) of4-nitrobenzylbromide was added. Twenty four hours later, the reactionmixture was poured into 100 ml of cold water and diluted with 50 mlCH₂Cl₂. The organic layer was decanted, washed with brine, dried overMgSO₄ and filtered. The solvent was eliminated under reduced pressureand the residue was purified by flash chromatography using heptane/EtOAc(1/1) as eluent. The pure fractions were collected and concentrated toyield 0.98 g (63%) of a yellow solid. Melting point: 111.4-11.7° C.

[1418] 67.24-(2-{[(4-aminobenzyl)(methyl)amino]methyl}-1,3-thiazol-4-yl)-2,6-di-tert-butylphenol:

[1419] The experimental protocol used is essentially the same asdescribed for Intermediate 18.2, starting from Intermediate 67.1.Purification by flash chromatography (CH₂Cl₂/EtOH (95/5)) yielded ayellow oil (52%).

[1420] 67.3N-(4-{[([4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}(methyl)amino]methyl}phenyl)thiophene-2-carboximidamide:

[1421] The experimental protocol used is the same as described forIntermediate 1.3, starting from Intermediate 67.2. The free base waspurified by flash chromatography using Heptane/EtOAc (1/9) as eluent toyield a yellow oil (17%). MH⁺: 547.20.

Example 68N-[3-({[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide Dihydrochloride (68)

[1422] 68.13-(3,5-di-tert-butyl-4-hydroxyphenyl)-N-(3-{[imino(thien-2-yl)methyl]amino}benzyl)propanamide:

[1423] To a solution of 2.78 g (10 mmol) of3,5-di-tert-butyl-4-hydroxyphenylpropionic acid, 3.04 g (10 mmol) ofN-[3-(aminomethyl)phenyl]thiophene-2-carboximidamide.2HCl (J. Med. Chem.(1998), 41(15), 2858), 1.48 g (11 mmol) of 1-hydroxybenzotriazole in 100ml of CH₂Cl₂, in a 250 ml flask, 4.21 g (22 mmol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 6.1 ml(44 mmol) of Et₃N were added. After overnight stirring at 20° C., thereaction mixture was diluted with 100 ml water, stirred and decanted.The organic layer was successively washed with NaHCO₃ saturatedsolution, water, KHSO₄ (1M), water and brine. After drying over Na₂SO₄and filtration, the organic solution was concentrated under reducedpressure. The residue was flash chromatographed over silica gel, usingheptane/EtOAc: 1/1 as eluent, to yield a cream light solid (85%).Melting point: 163-164° C.

[1424] 68.2N-[3-({[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamideDihydrochloride:

[1425] At 20° C., under argon atmosphere, a 1M solution of BH₃ in THF(14.7 ml; 14.7 mmol) was added dropwise to a stirred solution of 2.41 g(4.9 mmol) of intermediate 68.1 in 60 ml of anhydrous THF. Once additionwas completed, the reaction mixture was warmed to reflux for two hours.After cooling to 0° C. and careful addition of 10 ml MeOH, the mixturewas rewarmed to reflux for 30 minutes and then again cooled to 20° C.Concentration under reduced pressure was followed by the addition of 10ml MeOH and 10 ml of HCl 3N. Again, the mixture was heated to reflux for45 minutes. Finally, MeOH was discarded by concentration under reducedpressure and the remaining aqueous solution was basified with asaturated solution of Na₂CO₃ and extracted with CH₂Cl₂. The organicsolution was decanted and washed with brine, dried over MgSO₄, filteredand concentrated under reduced pressure. The residue was purified oversilica gel (eluent: CH₂Cl₂/EtOH/NH₄OH (20% aqueous sol.): 19/1/0.12).The suitable fractions were collected and concentrated. The residue wassalified by dissolving it in 5 ml MeOH followed by addition of 2 ml ofHCl (3N). Concentration of the solution under reduced pressure led to aresidue that crystallised by triturating in 20 ml of a 1/1 mixture ofacetone and EtOAc. After filtration and air drying a white powder wasobtained. Melting point: 158.5-159° C.

Example 69N-(3-{[(3,5-di-tert-butyl-4-hydroxybenzyl)amino]methyl}phenyl)thiophene-2-carboximidamide Dihydrochloride (69)

[1426] The experimental protocol used is the same as that described forExample 68, except that 3,5-di-tert-butyl-4-hydroxybenzoic acid replaced3,5-di-tert-butyl-4-hydroxyphenylpropionic acid. White powder. Meltingpoint: 233-234° C.

Example 70N-[3-({[2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethyl]amino}methyl)phenyl]thiophene-2-carboximidamide (70)

[1427] The experimental protocol used is the same as that described forExample 68, except that 3,5-di-tert-butyl-4-hydroxyphenylacetic acidreplaced 3,5-di-tert-butyl-4-hydroxyphenylpropionic acid. The free basewas obtained as a white powder. Melting point: 116-117° C.

Example 71N-[3-({[3-(4-hydroxy-3,5-diisopropylphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide Dihydrochloride (71)

[1428] 71.1 3-(4-hydroxy-3,5-diisopropylphenyl)propanoic Acid:

[1429] A solution of 2.64 g (10 mmol) of3-(4-hydroxy-3,5-diisopropylphenyl)propanoic acid methyl ester (cf. U.S.Pat. No. 3,642,868) and 0.84 g (20 mmol) of LiOH,H₂O in 80 ml of a 1/1mixture THF/H₂O was stirred at 20° C. for 7 hours. After evaporation ofTHF under reduced pressure, the aqueous solution was acidified withKHSO₄ (1M) and extracted twice with 50 ml EtOAc. The organic layer wasdecanted, washed with 20 ml brine, dried over MgSO₄ and filtered. Theresidue of evaporation was triturated with heptane to yield a whitepowder (67%). Melting point: 106-106.5° C.

[1430] 71.23-(4-hydroxy-3,5-diisopropylphenyl)-N-(3-{[imino(thien-2-yl)methyl]amino}benzyl)propanamide:

[1431] The experimental protocol used is the same as described forIntermediate 68.1, except that3-(4-hydroxy-3,5-diisopropylphenyl)propanoic acid replaced3,5-di-tert-butyl-4-hydroxyphenylpropionic acid. White powder. Meltingpoint: 144.5-145° C.

[1432] 71.3N-[3-({[3-(4-hydroxy-3,5-diisopropylphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide Dihydrochloride:

[1433] The experimental protocol used is the same as described forIntermediate 68.2, starting from Intermediate 71.2. White powder.Melting point: 160-160.5° C.

Example 72 N-(3-{[(4-hydroxy-3,5-diisopropylbenzyl)amino]methyl}phenyl)thiophene-2-carboximidamide (72)

[1434] The experimental protocol used is the same as that described forExample 69, except that 4-hydroxy-3,5-diisopropylbenzoic acid (J. Amer.Chem. Soc. (1957), 79, 5019) replaced 3,5-di-tert-butyl-4-hydroxybenzoicacid. Light grey powder. MH⁺: 422.20.

Example 73N-[3-({[2-(4-hydroxy-3,5-diisopropylphenyl)ethyl]amino}methyl)phenyl]thiophene-2-carboximidamide Dihydrochloride (73)

[1435] The experimental protocol used is the same as that described forExample 70, except that 4-hydroxy-3,5-diisopropylphenylacetic acid (cf.PCT application WO 96/11917) replaced3,5-di-tert-butyl-4-hydroxyphenylacetic acid. White powder. MH⁺: 436.30.

Example 74N-2-(3,5-di-tert-butyl-4-hydroxybenzoyl)-N-1-(4-{[imino(thien-2-yl)methyl]amino}phenyl)-L-leucinamide(74)

[1436] The experimental protocol used is the same as that described forExample 1, except that L-Leucine-4-nitroanilide replaced 4-nitroaniline.Deep yellow powder. Melting point: 164-166° C.

[1437] Pharmacological Study of the Products of the Invention

[1438] Study of the Effects on Neuronal Constitutive NO Synthase of aRat's Cerebellum

[1439] The inhibitory activity of the products of the invention isdetermined by measuring their effects on the conversion by the NOsynthase of the [³H]L-arginine in [³H]L-citrulline according to themodified method of Bredt and Snyder (Proc. Natl. Acad. Sci. USA, (1990)87: 682-685). The cerebellums of Sprague-Dawley rats (300 g—CharlesRiver) are rapidly removed, dissected at 4° C. and homogenized in avolume of extraction buffer (HEPES 50 mM, EDTA 1 mM, pH 7.4, pepstatin A10 mg/ml, leupeptin 10 mg/ml). The homogenates are then centrifuged at21000 g for 15 min at 4° C. Dosage is carried out in glass test tubes inwhich 100 μl of incubation buffer containing 100 mM of HEPES (pH 7.4), 2mM of EDTA, 2.5 mM of CaCl₂, 2 mM of dithiotreitol, 2 mM of reducedNADPH and 10 μg/ml of calmodulin are distributed. 25 μl of a solutioncontaining 100 nM of [³H]L-arginine (Specific activity: 56.4 Ci/mmole,Amersham) and 40 μM of non-radioactive L-arginine is added. The reactionis initiated by adding 50 μl of homogenate, the final volume being 200μl (the missing 25 μl are either water or the tested product). After 15min, the reaction is stopped with 2 ml of stopping buffer (20 mM ofHEPES, pH 5.5, 2 mM of EDTA). After placing the samples on a 1 ml columnof DOWEX resin, the radioactivity is quantified by a liquidscintillation spectrometer. The compounds of Examples 6, 7, 13, 14, 33,38 to 40, 58, 62, 63, 66 and 68 to 73 described above show an IC₅₀ lowerthan 3.5 μM. The compounds of Examples 35, 37, 41, 47, 52 to 54, 59, 61,64, 65 and 67 show an IC₅₀ lower than 10 μM.

[1440] Study of the Effects on Lipidic Peroxidation of the CerebralCortex of a Rat

[1441] The inhibitory activity of the products of the invention isdetermined by measuring their effects on the degree of lipidicperoxidation, determined by the concentration of malondialdehyde (MDA).The MDA produced by peroxidation of unsaturated fatty acids is a goodindication of lipidic peroxidation (H Esterbauer and K H Cheeseman,Meth. Enzymol. (1990) 186: 407-421). Male Sprague Dawley rats of 200 to250 g (Charles River) were sacrificed by decapitation. The cerebralcortex is removed, then homogenized using a Thomas potter in a 20 mMTris-HCl buffer, pH=7.4. The homogenate was centrifuged twice at 50000 gfor 10 minutes at 4° C. The pellet is maintained at −80° C. On the dayof the experiment, the pellet is replaced in suspension at aconcentration of 1 g/15 ml and centrifuged at 515 g for 10 minutes at 4°C. The supernatant is used immediately to determine the lipidicperoxidation. The homogenate of rat's cerebral cortex (500 μl) isincubated at 37° C. for 15 minutes in the presence of the compounds tobe tested or of solvent (10 μl). The lipidic peroxidation reaction isinitiated by adding 50 μl of FeCl₂ at 1 mM, EDTA at 1 mM and ascorbicacid at 4 mM. After 30 minutes of incubation at 37° C., the reaction isstopped by adding 50 R₁ of a solution of hydroxylated di tertio butyltoluene (BHT, 0.2%). The MDA is quantified using a colorimetric test, byreacting a chromogenic reagent (R), N-methyl-2-phenylindol (650 μl) with200 μl of the homogenate for 1 hour at 45° C. The condensation of an MDAmolecule with two molecules of reagent R produce a stable chromophorethe maximum absorbence wavelength of which is equal to 586 nm. (Caldwellet al., European J. Pharmacol. (1995), 285, 203-206). The compounds ofExamples 5, 8 to 10, 12 to 14, 16 to 21, 26, 27, 35, 43 to 46, 48 to 55,57 to 61 and 63 to 73 described above all show an IC₅₀ lower than 30 μM.

1. A compound selected from:N-{4-[({[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}amino)methyl]phenyl}thiophene-2-carboximidamide;N-{3-[({[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}amino)methyl]phenyl}thiophene-2-carboximidamide;N-(4-{[{[4-(3,5-di-tert-butyl-4-hydroxyphenyl)-1,3-thiazol-2-yl]methyl}(methyl)amino]methyl}phenyl)thiophene-2-carboximidamide;N-[3-({[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide;N-(3-{[(3,5-di-tert-butyl-4-hydroxybenzyl)amino]methyl}phenyl)thiophene-2-carboximidamide;N-[3-({[2-(3,5-di-tert-butyl-4-hydroxyphenyl)ethyl]amino}methyl)phenyl]thiophene-2-carboximidamide;N-[3-({[3-(4-hydroxy-3,5-diisopropylphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide;N-(3-{[(4-hydroxy-3,5-diisopropylbenzyl)amino]methyl}phenyl)thiophene-2-carboximidamide;N-[3-({[2-(4-hydroxy-3,5-diisopropylphenyl)ethyl]amino}methyl)phenyl]thiophene-2-carboximidamide;N-2-(3,5-di-tert-butyl-4-hydroxybenzoyl)-N-1-(4-{[imino(thien-2-yl)methyl]amino}phenyl)-L-leucinamide;or a pharmaceutically acceptable salt thereof.
 2. A compound of claim 1,which is selected from:N-[3-({[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide;N-[3-({[3-(4-hydroxy-3,5-diisopropylphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide;N-[3-({[2-(4-hydroxy-3,5-diisopropylphenyl)ethyl]amino}methyl)phenyl]thiophene-2-carboximidamide; or a pharmaceutically acceptablesalt thereof.
 3. A pharmaceutical composition containing as activeingredient at least one compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 4. The pharmaceutical composition containing asactive ingredient at least one compound selected from:N-[3-({[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide;N-[3-({[3-(4-hydroxy-3,5-diisopropylphenyl)propyl]amino}methyl)phenyl]thiophene-2-carboximidamide;N-[3-({[2-(4-hydroxy-3,5-diisopropylphenyl)ethyl]amino}methyl)phenyl]thiophene-2-carboximidamide; or a pharmaceutically acceptablesalt thereof.
 5. A method of inhibiting neuronal NO synthase in awarm-blooded animal comprising administering to said warm-blooded animala compound of claim 1, or a pharmaceutically acceptable salt thereof, inan amount sufficient to inhibit neuronal NO synthase.
 6. A method ofinhibiting inductible NO synthase in a warm-blooded animal comprisingadministering to said warm-blooded animal a compound of claim 1, or apharmaceutically acceptable salt thereof, in an amount sufficient toinhibit inductible NO synthase.
 7. A method of inhibiting lipidicperoxidation in a warm-blooded animal comprising administering to saidwarm-blooded animal a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, in an amount sufficient to inhibit lipidicperoxidation.
 8. A method of inhibiting both NO synthase and lipidicperoxidation in a warm-blooded animal comprising administering to saidwarm-blooded animal a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, in an amount sufficient to inhibit both NOsynthase and lipidic peroxidation.
 9. A method of treating stroke orneurodegenerative diseases in a warm-blooded animal comprisingadministering to said warm-blooded animal a compound of claim 1, or apharmaceutically acceptable salt thereof, in an amount sufficient toinhibit stroke or neurodegenerative diseases.
 10. The method of claim 9,wherein stroke is treated.
 11. The method of claim 9, whereinneurodegenerative diseases are treated.
 12. The method of claim 11,wherein the neurodegenerative diseases are selected from Alzheimer'sdisease, Huntington's chorea, Parkinson's disease, Creutzfeld Jacobdisease and amyotrophic lateral sclerosis.
 13. A method of preventing ortreating ischemic or hemorragic cardiac or cerebral infarctions in awarm-blooded animal comprising administering to said warm-blooded animala compound of claim 1, or a pharmaceutically acceptable salt thereof, inan amount sufficient to inhibit said ischemic or hemorragic cardiac orcerebral infarctions.
 14. The method of claim 13, wherein the preventingor treating ischemic or hemorragic cardiac or cerebral infarctionsprevented or treated are related with complications of coronary arterybypass grafting.